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Continual Monitoring of Intraepithelial Lymphocyte Immunophenotype and Clonality Is More Important Than Snapshot Analysis in the Surveillance of Refractory Coeliac Disease
  1. Hongxiang Liu1,
  2. Rebecca Brais1,
  3. Anne Lavergne-Slove2,
  4. Quitz Jeng3,
  5. Karen Payne1,
  6. Hongtao Ye3,
  7. Ziyuan Liu3,
  8. Joaquim Carreras3,
  9. Yuanxue Huang3,
  10. Chris M Bacon4,
  11. Rifat Hamoudi3,
  12. Vicky Save1,
  13. Lakshmi Venkatraman5,
  14. Peter G Isaacson6,
  15. Jeremy Woodward7,
  16. Ming-Qing Du3,*
  1. 1 Department of Histopathology, Addenbrooke's Hospital, Cambridge, United Kingdom;
  2. 2 Anatomie Pathologique, Hôpital Lariboisière, AP-HP, University Paris 7, France;
  3. 3 Department of Pathology, University of Cambridge, Cambridge, United Kingdom;
  4. 4 Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom;
  5. 5 Department of Histopathology, Royal Victoria Hospital, Belfast, United Kingdom;
  6. 6 Department of Histopathology, University College London Hospitals, London, United Kingdom;
  7. 7 Department of Gastroenterology, Addenbrooke's Hospital, Cambridge, United Kingdom
  1. Correspondence to: Ming-Qing Du, University of Cambridge, Department of Pathology, Division of Molecular Histopathology, Level 3 Lab Block, Box 231, Addenbrooke's Hospital, Hill's Road,, Cambridge, CB2 2QQ, United Kingdom; mqd20{at}


Objective: Aberrant immunophenotype and monoclonality of intraepithelial lymphocytes (IEL) are frequently found in refractory celiac disease (RCD). However, the utility of continual monitoring of IEL immunophenotype and clonality in the surveillance of RCD remains to be studied.

Design: The diagnostic and follow-up biopsies from 33 CD, 7 suspected RCD, 41 RCD and 20 enteropathy associated T-cell lymphoma (EATL) (including 11 evolved from RCD) patients were investigated by CD3e/CD8 double immunohistochemistry and PCR-based clonality analysis of the rearranged TCR genes.

Results: An aberrant immunophenotype (CD3ϵ+CD8- IEL ≥40%) and monoclonality were detected occasionally in CD biopsies, either transiently in CD patients not compliant with a gluten free diet or in those who subsequently developed suspected RCD, RCD or EATL. In contrast, the aberrant immunophenotype and monoclonality were respectively found in 30 of 41 (73%) and 24 of 37 (65%) biopsies at the time of RCD diagnosis. Among the RCD patients who did not show these abnormalities in their diagnostic biopsies, 8 of 10 (80%) and 5 of 11 (45%) cases gained aberrant immunophenotype and monoclonality respectively during follow-up. Irrespective of whether detected in diagnostic or follow-up biopsies, persistence of both abnormalities was characteristic of RCD. Importantly, the presence of concurrent persistent monoclonality and aberrant immunophenotype, especially <≥>80% CD3ϵ+CD8- IEL, was a strong predictor of EATL development in RCD patients (P=0.001).

Conclusions: Continual monitoring of both immunophenotype and clonality of IEL is more important than snapshot analysis for RCD diagnosis and follow-up, and could provide a useful tool for surveillance of patients at risk of EATL.

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