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Original Article
ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation
  1. Kamran Rostami1,
  2. Michael N Marsh2,3,
  3. Matt W Johnson2,
  4. Hamid Mohaghegh4,
  5. Calvin Heal5,
  6. Geoffrey Holmes6,
  7. Arzu Ensari7,
  8. David Aldulaimi8,
  9. Brigitte Bancel9,
  10. Gabrio Bassotti10,
  11. Adrian Bateman11,
  12. Gabriel Becheanu12,
  13. Anna Bozzola13,
  14. Antonio Carroccio14,
  15. Carlo Catassi15,
  16. Carolina Ciacci16,
  17. Alexandra Ciobanu12,
  18. Mihai Danciu17,
  19. Mohammad H Derakhshan18,19,
  20. Luca Elli20,
  21. Stefano Ferrero20,
  22. Michelangelo Fiorentino21,
  23. Marilena Fiorino14,
  24. Azita Ganji22,
  25. Kamran Ghaffarzadehgan23,
  26. James J Going24,
  27. Sauid Ishaq25,
  28. Alessandra Mandolesi15,
  29. Sherly Mathews1,
  30. Roxana Maxim17,
  31. Chris J Mulder26,
  32. Andra Neefjes-Borst26,
  33. Marie Robert27,
  34. Ilaria Russo16,
  35. Mohammad Rostami-Nejad4,
  36. Angelo Sidoni10,
  37. Masoud Sotoudeh19,
  38. Vincenzo Villanacci13,
  39. Umberto Volta21,
  40. Mohammad R Zali4,
  41. Amitabh Srivastava28
  1. 1Department of Gastroenterology and Pathology, Milton Keynes University Hospital, Milton Keynes, UK
  2. 2Department of Gastroenterology, Luton and Dunstable University Hospital, Luton, UK
  3. 3Wolfson College, University of Oxford, Oxford, UK
  4. 4Gastroenterology and Liver Diseases Research Centre, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, The Islamic Republic of Iran
  5. 5Centre for Biostatistics, Faculty of Biology, Academic Health Science Centre, University of Manchester, Manchester, UK
  6. 6Department of Gastroenterology, Royal Derby Hospital, Derby, UK
  7. 7Department of Pathology, Ankara University Medical School, Ankara, Turkey
  8. 8Department of Gastroenterology, Warwick Hospital, Warwick, UK
  9. 9Service de Pathologie, Centre de Biologie et Pathologie Groupe Hospitalier du Nord, Hospices Civils de Lyon, Lyon, France
  10. 10University of Perugia Medical School, Perugia, Italy
  11. 11Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
  12. 12Department of Pathology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
  13. 13Institute of Pathology Spedali Civili, Brescia, Italy
  14. 14Internal Medicine and Pathology Unit, University of Palermo, Giovanni Paolo II Hospital, Sciacca, Italy
  15. 15Department of Pediatrics and Surgical Pathology, Università Politecnica delle Marche, Ancona, Italy
  16. 16Department of Medicine and Surgery, Scuola Medica Salernitana, University of Salerno, Salerno, Italy
  17. 17Departments of Gastroenterology and Pathology, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania
  18. 18College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
  19. 19Digestive Disease Research Center, Tehran University Medical Science, Tehran, Iran
  20. 20Center for Prevention and Diagnosis of Coeliac Disease and Pathology Unit, Fondazione IRCCS Ca’ granda Ospedale Maggiore Policlinico, Milano, Italy
  21. 21Department of Medical and Surgical Sciences, University of Bologna and Diagnostic and Experimental, University of Bologna, Bologna, Italy
  22. 22Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  23. 23Pathology Department, Razavi Hospital, Mashhad, Iran
  24. 24Department of Pathology, Southern General Hospital, Lanarkshire, UK
  25. 25Dudley group of Hospitals, Birmingham City University, Birmingham, UK
  26. 26Department of Hepatogastroenterology and Pathology, Free University Medical Centre, Amsterdam, The Netherlands
  27. 27Department of Pathology and Medicine, Yale University School of Medicine, New Haven, USA
  28. 28Department of Pathology, Brigham & Women’s Hospital, Boston, USA
  1. Correspondence to Dr. Kamran Rostami, Department of Gastroenterology, Milton Keynes University Hospital, Milton Keynes MK6 5LD, UK; kamran.rostami{at}


Objectives Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive ‘normal’ IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens.

Design The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected.

Results The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2–88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion.

Conclusion Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose–response by IEL to environmental (gluten) antigenic influence.

  • coeliac disease
  • intraepithelial lymphocytes
  • ROC-curve analysis

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  • Contributors Forty-one pathologists and gastroenterologists participated in this study by contributing towards pathology and clinical data, discussion on study concept, statistical analysis and writing and revising the manuscript. The study was designed during the second consensus meeting incorporated in the International Course of Pathology in Bucharest. KR designed and coordinated the study, organised the second consensus meeting with help and support from GBe. He also collected the data and wrote the first draft of the manuscript. HM performed the first statistical analysis and contributed towards data interpretation. CH performed the second analysis and MNM rewrote the draft and revised the interpretation of data. MWJ and GH critically reviewed the manuscript and MWJ contributed with clinical and histology data. GBe provided data and co-organised the consensus meeting. MHD and JJG contributed with their data, critical revision, drafting and finalising the manuscript. ASr, AE, VV, UV, MD, ACa, ANB, CCi, MRN and LE contributed in the conceptualisation and design of the study, data collection and critical revision of the manuscript. BB, GBa, ABo, CCa, ACi, SF, MiF, MaF, AG, KG, SI, AM, SM, RM, CJM, IR, ASi and MRZ contributed with their pathology and clinical data and revision of the manuscript.

  • Competing interests None declared.

  • Ethics approval Research and development/audit departments of countries involved and the ethical committee of Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran under the following ethical number: IR.SBMU.RIGLD.REC.1395.87.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it published Online First. The affiliations for Sauid Ishaq, Masoud Sotoudeh and Stefano Ferrero have been updated.

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