Volume 128, Issue 5, Pages 1187-1198 (May 2005) Precursor Lesions in Patients With Multiple Endocrine Neoplasia Type 1--Associated Duodenal Gastrinomas  Martin Anlauf, Aurel Perren, Cora Lu Meyer, Sonja Schmid, Parvin Saremaslani, Marie L. Kruse, Eberhard Weihe, Paul Komminoth, Philipp U. Heitz, Günter Klöppel  Gastroenterology  Volume 128, Issue 5, Pages 1187-1198 (May 2005) DOI: 10.1053/j.gastro.2005.01.058 Copyright © 2005 American Gastroenterological Association Terms and Conditions

Figure 1 Multifocal duodenal gastrinomas. Multiple duodenal sections revealing 5 duodenal gastrinomas (arrows), each with a diameter of more than 2 mm. Gastroenterology 2005 128, 1187-1198DOI: (10.1053/j.gastro.2005.01.058) Copyright © 2005 American Gastroenterological Association Terms and Conditions

Figure 2 Gastrin-positive microtumors <2 mm in diameter. Serial sections in one patient revealing duodenal microtumors (A) within the mucosa (diameter, 0.4 mm) and (B) within the Brunner’s glands (diameter, 1 mm). The microtumors exhibit strong and homogeneous immunoreactivity for gastrin and a lobular growth pattern but lack angioinvasion and gross infiltration of (A) the submucosal layer and (B) the outer muscle layers. Gastroenterology 2005 128, 1187-1198DOI: (10.1053/j.gastro.2005.01.058) Copyright © 2005 American Gastroenterological Association Terms and Conditions

Figure 3 Microscopic proliferative gastrin cell lesions within the extratumorous mucosa and the Brunner’s glands. (A-E) Duodenal mucosa. (A) Immunostaining for gastrin showing the normal distribution of gastrin cells in the control duodenal mucosa. Various proliferative gastrin cell lesions in the mucosa are present in a subset of patients with duodenal gastrinomas: (B) circumscript diffuse hyperplasia, (C) linear and (D) nodular hyperplasia, and (E) a microinvasive lesion surrounded by thickened collagen. (F-J) Brunner’s glands. Corresponding hyperplastic lesions are present in the epithelium of Brunner’s glands. (F) Normal Brunner’s glands with scattered gastrin cells in the control mucosa. Various proliferative lesions in a subset of patients with duodenal gastrinomas: (G) diffuse hyperplasia, (H) diffuse and linear hyperplasia, (I) linear and nodular hyperplasia, and (J) microinvasive lesions in close relation to gastrin cell hyperplasia of Brunner’s glands. Gastroenterology 2005 128, 1187-1198DOI: (10.1053/j.gastro.2005.01.058) Copyright © 2005 American Gastroenterological Association Terms and Conditions

Figure 4 Quantitative analysis of the number of gastrin cells within the duodenal crypts and the Brunner’s glands of control patients in comparison with the extratumorous mucosa of patients with duodenal gastrinoma with and without evidence of neuroendocrine precursor lesions. The number of gastrin cells in precursor-positive patients is higher in the crypts and the Brunner’s glands (patients 3, 4, 7, and 10) than in the control specimens (references 1, 2, and 3). Precursor-negative patients (patients 22–25) do not show any increase in gastrin cell density in either compartment. Gastroenterology 2005 128, 1187-1198DOI: (10.1053/j.gastro.2005.01.058) Copyright © 2005 American Gastroenterological Association Terms and Conditions

Figure 5 Expression of CgA and Ki-67 in mucosal gastrin cell hyperplasia analyzed by double immunofluorescence confocal laser scanning microscopy. (A-C) Immunofluorescence for gastrin (green in A) revealing diffuse and linear hyperplasia of gastrin cells in the mucosa. A crypt with linear hyperplasia of gastrin cells is labeled by arrowheads in A-C. Immunofluorescence for CgA (red in B) reveals a small number of CgA-positive endocrine cells. The composite image (C) shows that only a minor subpopulation of gastrin cells is copositive for CgA. These copositive cells are stained yellow in C and are labeled by arrows in A-C. The green color in the composite image (C) demonstrates that CgA is absent in the majority of gastrin-positive cells. The red color in the composite image (C) shows a minor subpopulation of gastrin-negative but CgA-positive cells. (D-F) Immunofluorescence for gastrin (green in D) revealing 2 gastrin-positive micronodules with weak granular immunostaining. The micronodules are labeled by arrowheads in D-F. Immunofluorescence for Ki-67 (red in E) showing positivity in some nuclei. All nuclei are counterstained blue in D-F. The composite image (F) shows that some gastrin cells in micronodular hyperplasia are copositive for Ki-67. Note that a single endocrine cell reveals strong gastrin expression and is negative for Ki-67 (labeled by arrows in D-F). Gastroenterology 2005 128, 1187-1198DOI: (10.1053/j.gastro.2005.01.058) Copyright © 2005 American Gastroenterological Association Terms and Conditions