title: Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors.
abstract: 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.
authors.affiliation: Departments of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA. CIACOBU@jhmi.edu
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yachida
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.forename: Catherine M
authors.initials: CM
authors.lastname: White
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
authors.forename: Tyler
authors.initials: T
authors.lastname: Saunders
authors.forename: Richard
authors.initials: R
authors.lastname: Morgan
authors.forename: Roeland F
authors.initials: RF
authors.lastname: de Wilde
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Jessica
authors.initials: J
authors.lastname: Hicks
authors.forename: Angelo M
authors.initials: AM
authors.lastname: Demarzo
authors.forename: Chanjuan
authors.initials: C
authors.lastname: Shi
authors.forename: Rajni
authors.initials: R
authors.lastname: Sharma
authors.forename: Daniel
authors.initials: D
authors.lastname: Laheru
authors.forename: Barish H
authors.initials: BH
authors.lastname: Edil
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.forename: Richard D
authors.initials: RD
authors.lastname: Schulick
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Laura H
authors.initials: LH
authors.lastname: Tang
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018287:Carcinoma, Large Cell / Q000235:genetics* / Q000473:pathology*; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000473:pathology*; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*