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Int J Clin Exp Pathol 2012;5(5):411-421

Original Article
Characterization of lymphoid follicles with red ring signs as first manifestation of early
Crohn’s disease by conventional histopathology and confocal laser endomicroscopy

Ekaterina Krauss, Abbas Agaimy, Helmut Neumann, Ulrike Schulz, Hermann Kessler, Arndt Hartmann, Markus F Neurath, Martin Raithel,
Jonas Mudter

Department of Medicine 1, University of Erlangen-Nuremberg, Ulmenweg 18, D-91054 Erlangen, Germany; Institute of Pathology, University of
Erlangen-Nuremberg, Krankenhausstr.8-10, 91054 Erlangen; Medistat medical statistic, Amalienweg 16, 24119 Kronshagen, Germany;
Department of Abdominal Surgery; University of Erlangen-Nuremberg, Krankenhausstr.12, D-91054 Erlangen, Germany. *contributed equally to
this work.

Received April 20, 2012; accepted May 12, 2012; Epub May 23, 2012; Published June 30, 2012

Abstract: Background and aims: Clinical observations suggest that the lymphoid follicles (LFs) may play a crucial role in the pathogenesis of
inflammatory bowel disease (IBD), especially in Crohn’s disease (CD) as the site of initial mucosal inflammation. The aim of this study was to
compare the morphology of LFs in CD, ulcerative colitis (UC) and control patients using confocal laser endomicroscopy (CLE) in correlation to
histological and immunohistochemical findings of biopsies. Methods: 79 patients with IBD (46 with CD, 32 with UC and 1 patient with
indeterminate colitis) and 67 controls patients were enrolled prospectively in this study. Median age was 32.5 years (range 19-65) and 37.4
years (range 20-65 years) respectively. To analyze the LFs, standardized images from the terminal ileum and the colon were taken using white-
light video endoscopes. Additionally, CLE was performed to analyze subsurface structure of LFs. Targeted biopsies of LFs were analyzed using
haematoxylin and eosin stain and immunohistochemistry. Results: LFs were seen in all parts of the lower GI tract, but mostly in the terminal
ileum and cecum. Endoscopy in 15 out of 17 patients with the first manifestation of CD showed LFs surrounded by red ring (so-called red ring
sign, RRS). Histologically, LFs with RRS showed hypervascularization at the base of the LFs associated with numerous CD15-positive
granulocytes. Similar features were not seen in LFs without RRS and in the control group. In some LFs with RRS early aphthous ulcers were
seen. Using CLE, RRS showed abolished normal crypt architecture, crypt distortion, increased cellular infiltrate within the lamina propria, and
dilated vessels. Conclusion: LFs with RRS probably represent an early sign of aphthous ulcers in early CD and, thus, may be considered as
early markers of first manifestation and flares in CD.

Keywords: Endomicroscopy, CLE, red ring sign, Crohn`s disease, lymphoid hyperplasia, inflammatory bowel disease, ulcerative colitis,
lymphoid follicle, pathology

Address all correspondence to:
Dr. Jonas Mudter
Department of Medicine I
University of Erlangen-Nuremberg
Ulmenweg 18, D-91054 Erlangen, Germany.
Tel: +49 9131 85 35000; Fax: +49 9131 8535116
E-mail: jonas.mudter@uk-erlangen.de