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 (NEC) 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 to 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 nine small cell NEC, 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 NEC, whereas Smad4/Dpc4, DAXX and ATRX labeling were 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. By contrast, DAXX and ATRX 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 nine small cell NECs (100%) and in five of 10 (50%) large cell NECs compared to only two of 11 (18%) PanNETs. Bcl-2 overexpression was significantly correlated with higher mitotic rate and Ki-67 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.

ISL1 expression is not restricted to pancreatic well-differentiated neuroendocrine neoplasms, but is also commonly found in well and poorly differentiated neuroendocrine neoplasms of extrapancreatic origin

“…In a recent study, pancreatic NETs revealed an absent or only very low TP53 signature in the presence of high expression of PDX1, whereas pancreatic neuroendocrine carcinomas, regardless whether of small or large cell type, showed the opposite. 16 Our results are consistent with these data. These features have also been observed in large cell neuroendocrine carcinomas and atypical carcinoids of the head and neck, and have been used as a distinguishing criterion.…”

“…In addition, we also studied some well-differentiated extrapancreatic neuroendocrine neoplasms such as thyroid medullary carcinomas and paragangliomas/pheochromocytomas whose ISL1 status is not well known. In addition to ISL1, we stained a substantial fraction of the cases with TP53, which is known to be overexpressed in poorly differentiated neuroendocrine neoplasms of the pancreas 16 and neuroendocrine carcinomas from extrapancreatic sites. 17 We demonstrate in particular that ISL1 expression is mostly lost in pancreatic poorly differentiated neuroendocrine neoplasms, while it is almost ubiquitously observed in their extrapancreatic neuroendocrine counterparts.…”

A Case Report of a Poorly Differentiated Neuroendocrine Carcinoma Diagnosed in the Bone Marrow

“…However, rarely do these tumors involve the bone marrow [5]. Interestingly, while small cell and large cell neuroendocrine tumors share the same genetic changes, they are distinct from those reported in well differentiated neuroendocrine tumors [6].…”

Extrapulmonary neuroendocrine small and large cell carcinomas: a review of controversial diagnostic and therapeutic issues

“…They are rare or extremely rare outside the lung and can develop in virtually any location. Relatively large series were reported in the gastroenteropancreatic (GEP) area, including the esophagus [6], stomach [7,8], colon and rectum [9], and pancreas [10]. In addition, EPNECs of the small or large type were investigated in the prostate [11,12], bladder [13] and uterine cervix [14,15].…”

“…In extrapulmonary locations, only a single recent study [10] analyzed 19 pancreatic NECs (9 small and 10 large cells), as well as 11 well differentiated NETs, for alterations of KRAS, CDKN2A/p16, P53, SMAD4/DPC4, DAXX, ATRX, PTEN, Bcl2, and RB1 genes. Small and large cell NECs had genetically similar profiles but distinct from those observed in well-differentiated NETs.…”