Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors.
Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors.
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DOI：
10.1097/pas.0b013e3182417d36
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发表时间：
2012-02
期刊：
影响因子：
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通讯作者：
Iacobuzio-Donahue CA
中科院分区：
文献类型：
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作者：
Yachida S;Vakiani E;White CM;Zhong Y;Saunders T;Morgan R;de Wilde RF;Maitra A;Hicks J;Demarzo AM;Shi C;Sharma R;Laheru D;Edil BH;Wolfgang CL;Schulick RD;Hruban RH;Tang LH;Klimstra DS;Iacobuzio-Donahue CA
胰腺低分化神经内分泌癌是一种罕见的恶性肿瘤，预后差。本研究的目的是确定低分化NEC的临床病理学和遗传学特征，并将其与其他类型的胰腺肿瘤进行比较。我们通过免疫组织化学和/或靶向外显子组测序研究了9例小细胞NEC、10例大细胞NEC和11例胰腺高分化神经内分泌肿瘤（PanNET）手术切除标本中KRAS、CDKN 2A/p16、TP 53、SMAD 4/DPC 4、DAXX、ATRX、PTEN、Bcl 2和RB 1的改变。在小细胞和大细胞NEC中，p53和Rb的异常免疫标记模式是常见的（p53，19例中的18例，95%; Rb，19例中的14例，74%），而Smad 4/Dpc 4，DAXX和ATRX标记在几乎所有这些相同的癌中是完整的。p53和Rb蛋白的异常免疫标记与TP 53和RB 1基因的基因内突变相关。相比之下，DAXX和ATRX在45%的PanNET中丢失，而p53和Rb免疫标记在这些相同的情况下是完整的。Bcl-2蛋白在所有9个小细胞NEC中（100%）和10个大细胞NEC中的5个（50%）中观察到过表达，而11个PanNET中只有2个（18%）。Bcl-2过表达与其存在的肿瘤中较高的有丝分裂率和Ki-67标记指数显著相关。小细胞NEC在遗传上与大细胞NEC相似，这些遗传变化与PanNET中报道的不同。Bcl-2在低分化NEC，特别是小细胞NEC中过表达的发现表明Bcl-2拮抗剂/抑制剂可能是这些患者的可行治疗选择。
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.