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Small Cell and Large Cell Neuroendocrine Carcinomas of the Pancreas are Genetically Similar and Distinct From Well-differentiated Pancreatic Neuroendocrine Tumors

Yachida, Shinichi MD, PhD*; Vakiani, Efsevia MD, PhD; White, Catherine M. BS*; Zhong, Yi MD, PhD*; Saunders, Tyler HS*; Morgan, Richard MS*; de Wilde, Roeland F. MD*; Maitra, Anirban MBBS*; Hicks, Jessica BS*; DeMarzo, Angelo M. MD, PhD*,‡; Shi, Chanjuan MD, PhD§; Sharma, Rajni PhD*; Laheru, Daniel MD; Edil, Barish H. MD; Wolfgang, Christopher L. MD, PhD; Schulick, Richard D. MD; Hruban, Ralph H. MD*,‡; Tang, Laura H. MD, PhD; Klimstra, David S. MD; Iacobuzio-Donahue, Christine A. MD, PhD*,‡,∥

The American Journal of Surgical Pathology: February 2012 - Volume 36 - Issue 2 - p 173–184
doi: 10.1097/PAS.0b013e3182417d36
Original Articles

Poorly differentiated neuroendocrine carcinomas (NECs) of the pancreas are rare malignant neoplasms with a poor prognosis. The aim of this study was to determine the clinicopathologic and genetic features of poorly differentiated NECs and compare them with other types of pancreatic neoplasms. We investigated alterations of KRAS, CDKN2A/p16, TP53, SMAD4/DPC4, DAXX, ATRX, PTEN, Bcl2, and RB1 by immunohistochemistry and/or targeted exomic sequencing in surgically resected specimens of 9 small cell NECs, 10 large cell NECs, and 11 well-differentiated neuroendocrine tumors (PanNETs) of the pancreas. Abnormal immunolabeling patterns of p53 and Rb were frequent (p53, 18 of 19, 95%; Rb, 14 of 19, 74%) in both small cell and large cell NECs, whereas Smad4/Dpc4, DAXX, and ATRX labeling was intact in virtually all of these same carcinomas. Abnormal immunolabeling of p53 and Rb proteins correlated with intragenic mutations in the TP53 and RB1 genes. In contrast, DAXX and ATRX labeling was lost in 45% of PanNETs, whereas p53 and Rb immunolabeling was intact in these same cases. Overexpression of Bcl-2 protein was observed in all 9 small cell NECs (100%) and in 5 of 10 (50%) large cell NECs compared with only 2 of 11 (18%) PanNETs. Bcl-2 overexpression was significantly correlated with higher mitotic rate and Ki67 labeling index in neoplasms in which it was present. Small cell NECs are genetically similar to large cell NECs, and these genetic changes are distinct from those reported in PanNETs. The finding of Bcl-2 overexpression in poorly differentiated NECs, particularly small cell NEC, suggests that Bcl-2 antagonists/inhibitors may be a viable treatment option for these patients.

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*Departments of Pathology


Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY

§Department of Pathology, Vanderbilt University Medical Center, Nashville, TN

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. Supported by National Institutes of Health Grants CA140599 and P50 CA62924, The Uehara Memorial Foundation, The George Rubis Endowment for Pancreatic Cancer Research, The Michael Rolfe Pancreatic Cancer Foundation, Sigma Beta Sorority, The Joseph C. Monastra Foundation, The Alfredo Scatena Memorial, and The Patty Boshell Pancreas Cancer Foundation.

Correspondence: Christine A. Iacobuzio-Donahue, MD, PhD, Department of Pathology, GI/Liver Division, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRBII 343, Baltimore, MD 21231 (e-mail:

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© 2012 Lippincott Williams & Wilkins, Inc.