The Intracellular Intensity of CD3 on Aberrant Intraepithelial Lymphocytes Is a Prognostic Factor of the Progression to Overt Lymphoma in Refractory Celiac Disease Type II (Pre-Enteropathy-Associated T Cell Lymphoma)

Abstract

<b><i>Background:</i></b> Refractory celiac disease type II (RCD-II) is a very rare yet severe complication of celiac disease (CD) with a 50% rate of progression to Enteropathy-associated T-cell lymphoma (EATL). Timely diagnosis and treatment of RCD-II is of the essence and requires the identification of a population of frequently clonal, phenotypically aberrant intraepithelial lymphocytes (IELs). Flow Cytometry of intestinal IELs is the recommended method to identify the aberrant surface CD3-negative (sCD3^–) intracytoplasmic CD3-positive (icCD3ε⁺) IELs, and a proportion of &#x3e;20% is diagnostic of RCD-II. There is substantial heterogeneity in the clinical course of RCD-II, and insufficient information on prognostic factors. <b><i>Aim:</i></b> To establish flow cytometric predictors of the clinical evolution of RCD-II, to help guide treatment approaches. <b><i>Patients and Methods:</i></b> Retrospective single-center study of clinical and immunological features of 6 RCD-II patients and a control group, both identified from a 2,000-patient cohort over 16 years. IEL subset frequencies and the intensity of staining for surface (s) and intracytoplasmic (ic) CD3ε+ on IEL subsets were quantified and correlated with the clinical outcome. <b><i>Results:</i></b> Unexpectedly, the frequency of aberrant sCD3^– icCD3ε⁺ cells at diagnosis did not correlate with histological or clinical affection. However, a higher intensity of icCD3ε⁺ staining in the aberrant IELs relative to expression on normal IELs correlated with monoclonality and with worse clinical outcomes. <b><i>Conclusion:</i></b> The ratio of icCD3ε⁺ on aberrant IELs vs. normal IELs appears to be a useful indicator of prognosis at the time of diagnosis, and may represent a novel tool in the follow-up of RCD-II patients after therapy.