Insulinomatosis A Multicentric Insulinoma Disease that Frequently Causes Early Recurrent Hyperinsulinemic Hypoglycemia Martin Anlauf, MD,*w Juliane Bauersfeld, MD,* Andreas Raffel, MD,z Christian A. Koch, MD,y Tobias Henopp, MD,* Ibrahim Alkatout, MD,*J Anja Schmitt, MD,z Achim Weber, MD,z Marie L. Kruse, MD,# Stefan Braunstein, MD,** Klaus Kaserer, MD, ww Michael Brauckhoff, MD,zz Henning Dralle, MD,zz Holger Moch, MD,z PhilippU. Heitz, MD,z Paul Komminoth, MD,yy Wolfram T. Knoefel, MD,z Aurel Perren, MD,JJ and Gu ¨ nter Klo ¨ppel, MD* Background: Multicentric insulinoma disease was characterized with regard to its histopathology, multiple endocrine neoplasia type 1 (MEN1) status, precursor lesions, and the risk of hyper- insulinemic hypoglycemia recurrence. Methods: Fourteen patients with multicentric insulinoma disease were compared with 267 patients with sporadic and familial insulinomas. The tumors were classified according to the World Health Organization (WHO) criteria. The MEN1 status was defined clinically and by germline mutation analysis. Detection of the MEN1 gene locus was performed using fluorescence in situ hybridization. The surgical interventions and the duration of disease-free survival were recorded. Results: Fourteen patients (5%) without evidence of MEN1 showed 53 macrotumors and 285 microtumors expressing exclusively insulin. In addition, they had small proliferative insulin-expressing monohormonal endocrine cell clusters (IMECCs). No allelic loss of the MEN1 locus was detected in 64 tumors. All but one patient had benign disease. Recurrent hypoglycemia occurred in 6/14 patients (11 recurrences; mean time to relapse 8.4 y). Thirteen patients with MEN1 (4.6%) showed 41 insulinomas and 133 tumors expressing islet hormones other than insulin. IMECCs were not detected. Allelic loss of the MEN1 locus was found in 17/19 insulinomas. Recurrent hypoglycemia occurred in 4/13 patients (4 recur- rences; mean time to relapse 14.5 y). Solitary insulinomas were found in 254/281 patients (90.4%). IMECCs were absent. There was no recurrent hypoglycemia in 84 patients with benign insulinomas. Conclusions: Insulinomatosis is characterized by the synchro- nous and metachronous occurrence of insulinomas, multiple insulinoma precursor lesions, and rare development of metas- tases, but common recurrent hypoglycemia. This disease differs from solitary sporadic and MEN1-associated insulinomas. Key Words: hyperinsulinism, hypoglycemia, insulinoma, multi- ple endocrine neoplasia type 1, pancreatic endocrine tumors (Am J Surg Pathol 2009;33:339–346) I nsulin-producing tumors of the pancreas are the most frequent cause of persistent hyperinsulinemic hypogly- cemia (PHH) in adults. They are usually solitary benign neoplasms that are not associated with hereditary diseases. 13 Approximately 10% of patients with multiple endocrine neoplasia type 1 (MEN1) develop insulino- mas. 2,13 Here, we describe 14 patients with PHH, showing multiple small and large insulinomas and multiple potential insulinoma precursor lesions. These patients had a higher rate of recurrent PHH after insulinoma resection than 254 patients with solitary insulinomas or 13 patients with MEN1-associated insulinomas. We discuss the differences in histopathology, clinical and genetic MEN1 status, somatic MEN1 deletions, and the risk of hyperinsulinemic hypoglycemia recurrence. Copyright r 2009 by Lippincott Williams & Wilkins From the Departments of *Pathology; JGeneral and Visceral Surgery; #1st Department of Medicine, Laboratory for Molecular Gastro- enterology and Hepatology, University of Kiel; wInstitute of Pathology, Johanna Etienne Hospital, Medical Center Neuss; Departments of zGeneral, Visceral and Pediatric Surgery; **Patho- logy, University of Du¨sseldorf; zzDepartment of General and Visceral Surgery, University of Halle; JJDepartment of Pathology, Technische Universita¨t Mu¨nchen, Klinikum Rechts der Isar, Germany; yDivision of Endocrinology, University of Mississippi Medical Center, Jackson, MS; zDepartment of Surgical Pathology, University Hospital, Zu¨rich; yyDepartment of Pathology, Triemli Hospital, Zu¨rich, Switzerland; and wwDepartment of Clinical Pathology, Medical University of Vienna, Vienna, Austria. Supported by the Hensel Stiftung Kiel (F370011, M.A. and G.K.), the Swiss National Foundation (SNF 31-61884, A.P. and P.K.), the German Society of Pathology (M.A.), and Novartis Oncology, Nu¨rnberg, Germany (M.A. and G.K.). Martin Anlauf and Juliane Bauersfeld contributed equally to this study. Juliane Bauersfeld has a student fellowship from the Medical Faculty of the University of Kiel (F344101) and the Hensel Stiftung, Kiel, Germany. Some of the results of this study are part of her MD thesis. Tobias Henopp has a fellowship sponsored by Ipsen GMBH, Ettlingen, Germany. Aurel Perren and Gu¨nter Klo¨ppel share senior authorship for this manuscript. Correspondence: Gu¨nter Klo¨ppel, MD, Department of Pathology, University of Kiel, Michaelisstr. 11, 24105 Kiel, Germany (e-mail: guenterkloeppel@path.uni-kiel.de). ORIGINAL ARTICLE Am J Surg Pathol  Volume 33, Number 3, March 2009 339