ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation

Abstract

ObjectivesCounting 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.DesignThe 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.ResultsThe 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.ConclusionOur 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.

AGA Clinical Practice Update on Diagnosis and Monitoring of Celiac Disease—Changing Utility of Serology and Histologic Measures: Expert Review

“…Description of the biopsies including positioning, Marsh classification,villus-crypt (VCr)-ratio and counting of lymphocytes (above 25 per HPF) to define lymphocytosis is recommended. CD3 staining for T-cells may be included 18 . Gamma/delta T-cell markers 19 as well as IgA transglutaminase antibody deposits 20 may be supportive in the analysis.…”

ROC-king onwards: intraepithelial lymphocyte counts, distribution and role in coeliac disease mucosal interpretation

“…Currently, there is an ongoing debate on the number of IEL that can safely be considered diagnostic for coeliac disease (CD). In our opinion, the recently published attempt by Rostami et al 1 turns out to be insignificant due to the following shortcomings: the controls used were neither sex-matched nor age-matched. Controls showing any abnormality which might result in an increase in IEL counts were excluded.…”

“…Moreover, in their recent paper,1 Rostami et al claim that the Marsh-Oberhuber classification originated in Dutch studies and was adopted by us without proper citation. We strongly challenge their assumption and wish to set the record straight.…”

Celiac Disease

“…53 Characteristic histologic features include a combination of increased tip-predominant intraepithelial lymphocytes (>25 per 100 enterocytes), partial or total villous atrophy, crypt hyperplasia, and chronic inflammation in the lamina propria. 55 Multiple CD histologic classification systems are available (Marsh, Oberhuber-Marsh, Corazza, and Ensari) to improve communication between pathologists and clinicians. 56 Although the utility of grading of villous atrophy has been challenged recently, 57,58 a complete histopathologic report is mandatory in everyday clinical practice.…”