Multiple neuroendocrine tumors of the pancreas in vonHippel-Lindau disease patients - Histopathological and molecular genetic analysis
Multiple neuroendocrine tumors of the pancreas in vonHippel-Lindau disease patients - Histopathological and molecular genetic analysis
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DOI：
10.1016/s0002-9440(10)65563-0
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发表时间：
1998-07-01
影响因子：
6
通讯作者：
Zhuang, ZP
中科院分区：
文献类型：
--
作者：
Lubensky, IA;Pack, S;Zhuang, ZP
虽然胰腺神经内分泌转归(NETs)在von Hippel-Lindau病(VHL)中已有报道，但其病理特征尚未明确。此外，VHL基因的改变是否与胰腺网络发育有关尚不清楚，为了评估VHL患者的NETS，我们对14例患者的30个胰腺肿瘤进行了组织病理学分析。此外，采用荧光原位杂交和聚合酶链式反应单链构象多态分析方法，对6例VHL基因突变患者的Net和正常胰腺组织DNA进行了VHL基因第二拷贝的等位基因缺失分析。在形态上，肿瘤的特征是实性、小梁性和/或腺状结构和突出的间质胶原带。60%的肿瘤细胞学检查显示至少有局限性透明细胞，所有肿瘤的泛内分泌免疫组织化学标记(嗜铬粒素A和/或突触素)均为阳性；35%的肿瘤胰腺多肽、生长抑素、胰岛素和/或胰高血糖素呈局灶性阳性；65%的肿瘤未见胰腺和胃肠激素的免疫染色。电子显微镜下可见致密的核心神经分泌颗粒，透明细胞还可见丰富的胞浆内脂质。所有接受遗传分析的Net都显示VHL基因的第二个拷贝的等位基因丢失。我们得出结论，在VHL患者中存在多个无功能的胰腺网络。间质胶原带和透明细胞形态是VHL相关Net的重要组织学特征，胰腺Net中VHL基因等位基因缺失的存在为该基因在肿瘤发生中的作用提供了直接的分子证据，并确立了Net作为VHL疾病的独立驯服类型。
Although pancreatic neuroendocrine turners (NETs) in von Hippel-Lindau (VHL) disease have been reported, their pathological features have not been characterized. In addition, it is unknown whether alterations of the VHL gene are responsible for pancreatic NET development, To evaluate NETs in VHL patients, we performed histopathological analysis of 30 pancreatic tumors in 14 patients. In addition, DNA from NETs and normal pancreatic tissue from 6 patients with documented germ-line VHL gene mutations was studied for allelic deletions of the second copy of the VHL gene by fluorescence in situ hybridization and polymerase chain reaction-based single-strand conformational polymorphism analysis. Morphologically, the tumors were characterized by solid, trabecular, and/or glandular architecture and prominent stromal collagen bands. Sixty percent of the tumors revealed at least focally clear-cell cytology, All tumors were positive for panendocrine immunohistochemistry markers (chromogranin A and/or synaptophysin); 35% of NETs demonstrated focal positivity for pancreatic polypeptide, somatostatin, insulin, and/or glucagon; and no immunostaining for pancreatic and gastrointestinal hormones was observed in 65% of tumors. Dense core neurosecretory granules were evident by electron microscopic examination, and the clear cells additionally revealed abundant Intracytoplasmic lipid. All NETs that were subjected to genetic analysis showed allelic loss of the second copy of the VHL gene. We conclude that multiple, nonfunctional pancreatic NETs occur in VHL patients. Stromal collagen bands and clear-cell morphology are important histological features of VHL-associated NETs, The presence of allelic deletions of the VHL gene in pancreatic NETs provides direct molecular evidence for a role of the gene in their tumorigenesis and establishes NET as an independent tamer type of VHL disease.