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Glucagon Cell Adenomatosis: A Newly Recognized Disease of the Endocrine Pancreas

Departments of Pathology (T.H., M.A., G.K.) and Forensic Medicine (R.S.), University of Kiel, 24105 Kiel, Germany; Department of Pathology (T.H.), University of Tübingen, 72076 Tübingen, Germany; Institute of Pathology (M.A.), 41462 Facharztzentrum Neuss, Germany; Department of Surgical Pathology (A.S., P.U.H., A.P.), University Hospital of Zürich, 8091 Zurich, Switzerland; 1st Institute of Pathology and Experimental Cancer Research (A.Z.), Semmelweis University, 1085 Budapest, Hungary; Department of Pathology (A.C.), Hospital Beaujon, 92110 Clichy, France; Service of Gastroenterology (P.R.), Hospital Beaujon, 92118 Clichy, France; Praxis für Innere Medizin (K.-P.S.), 26388 Wilhelmshaven, Germany; Department of Molecular Cell Biology (Y.M.H.J., E.-J.M.S.), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands; Institute of Pathology (N.S.P.), Helmholtz Zentrum Munich, 85764 Neuherberg, Germany; Department of Pathology (A.P.), Technische Universität, 81675 München, Germany; and Department of Pathology (P.K.), Triemli Hospital, 8063 Zürich, Switzerland

Address all correspondence and requests for reprints to: Tobias Henopp, M.D., Department of Pathology, University of Tübingen, Liebermeisterstr. 8, 72076 Tübingen, Germany. E-mail: Tobias.Henopp{at}med.uni-tuebingen.de.

Background: Glucagon-producing tumors are either solitary neoplasms of the pancreas, occasionally associated with a glucagonoma syndrome, or multiple neoplasms associated with multiple endocrine neoplasia type 1 (MEN1). We observed a previously undescribed multicentric glucagon-producing tumor disease that is not related to MEN1.

Methods: Pancreatic tissue from four patients showing multiple neuroendocrine microadenomas and in two cases also macrotumors were screened for hormones using immunohistochemical and morphometric methods. MEN1, von Hippel-Lindau, and p27 germ line and somatic mutation analysis was performed. Deletion of MEN1 (11q13), von Hippel-Lindau (3p25), and the centromere 11 and 3 gene locus was determined by fluorescence in situ hybridization. DNA copy number changes were studied using array comparative genomic hybridization.

Results: The pancreatic tissue from the four patients contained more than 870 microadenomas and 10 macrotumors, all of which expressed exclusively glucagon and none of which showed evidence of malignancy. In addition, many islets were unusually large and showed glucagon cell hyperplasia. There was no clinical or molecular evidence of any hereditary tumor disease, and changes in the MEN1 gene were only seen in individual tumors. Array comparative genomic hybridization of one macrotumor and 20 pooled microadenomas revealed a homogeneous diploid chromosome set.

Conclusions: The findings are sufficiently distinctive to suggest a new neoplastic disease of the endocrine pancreas that we recommend calling glucagon cell adenomatosis. Clinically, this disease may be an incidental finding, or it may lead to a glucagonoma syndrome.