Original ArticlesACTH-secreting Pancreatic Neoplasms Associated With Cushing Syndrome Clinicopathologic Study of 11 Cases and Review of the LiteratureMaragliano, Roberta MD*; Vanoli, Alessandro MD†; Albarello, Luca MD‡; Milione, Massimo MD§; Basturk, Olca MD∥; Klimstra, David S. MD∥; Wachtel, Antonio MD¶; Uccella, Silvia MD, PhD*; Vicari, Emanuela MLT*; Milesi, Marina MD#; Davì, Maria Vittoria MD**; Scarpa, Aldo MD††; Sessa, Fausto MD*; Capella, Carlo MD*; La Rosa, Stefano MD‡‡Author Information *Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy ‡‡Department of Pathology, Ospedale di Circolo, Varese, Italy †Department of Molecular Medicine, University of Pavia, Pavia, Italy ‡Department of Pathology, San Raffaele Hospital, Milan, Italy §Department of Pathology, National Institute of Cancer, Milan, Italy #Department of Pathology, Multimedica, Milan, Italy **Department of Medicine, “G.B. Rossi” University Hospital, Verona, Italy ††ARC-NET Research Center and Department of Pathology and Diagnostics, University of Verona, Verona, Italy ∥Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY ¶Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website, www.ajsp.com. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Stefano La Rosa, MD, Department of Pathology, Servizio di Anatomia Patologica, Ospedale di Circolo, Viale Borri 57, 21100 Varese, Italy (e-mail: firstname.lastname@example.org). The American Journal of Surgical Pathology: March 2015 - Volume 39 - Issue 3 - p 374-382 doi: 10.1097/PAS.0000000000000340 Buy SDC Metrics Abstract Adrenocorticotropic hormone (ACTH)-secreting pancreatic neuroendocrine tumors (PanNETs), although rare, are responsible for about 15% of ectopic Cushing syndrome (CS). They represent a challenging entity because their preoperatory diagnosis is frequently difficult, and clear-cut morphologic criteria useful to differentiate them from other types of PanNETs have not been defined. Ectopic ACTH secretion associated with CS can also be rarely due to pancreatic acinar cell carcinoma (ACC) and pancreatoblastoma, rare tumor types with morphologic features sometimes overlapping those of PanNETs and, for this reason, representing a diagnostic challenge for pathologists. We herein describe the clinicopathologic and immunohistochemical features of 10 PanNETs and 1 ACC secreting ACTH and associated with CS together with an extensive review of the literature to give the reader a comprehensive overview on ACTH-producing pancreatic neoplasms. ACTH-secreting PanNETs are aggressive neoplasms with an immunohistochemical profile that partially overlaps that of pituitary corticotroph adenomas. They are generally large and well-differentiated neoplasms without distinctive histologic features but with signs of aggressiveness including vascular and perineural invasion. They are more frequent in female individuals with a mean age of 42 years. At 5 and 10 years after diagnosis, 35% and 16.2% of patients, respectively, were alive. ACTH-secreting ACCs and pancreatoblastomas are very aggressive pediatric tumors with a poor prognosis. Using an appropriate immunohistochemical panel including ACTH, β-endorphin, trypsin, and BCL10 it is possible to recognize ACTH-secreting PanNETs and to distinguish them from the very aggressive ACTH-secreting ACCs. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.