PDF(Pubmed)
Abstract：
UNASSIGNED: Early-stage small intestinal neuroendocrine tumors (SI-NETs) are generally asymptomatic and difficult to diagnose. As a result, patients often present with late-stage incurable disease. SI-NETs originate from enterochromaffin (EC) cells, which develop enteroendocrine cell (EEC) clusters consisting of a subset of EC cells at the crypt bottom at an early stage of tumor progression. In a familial form of SI-NET, EEC clusters arise in a multifocal and polyclonal fashion. We sought to determine whether early detection and analysis of cryptal EEC clusters could provide insight into the development of SI-NETs and allow successful pre-symptomatic screening for at risk family members of patients with SI-NETs.
UNASSIGNED: Isolated crypts from endoscopic ileal biopsies or surgically removed specimens from 43 patients with familial SI-NET and 20 controls were formalin-fixed, immunostained for chromogranin A, and examined by confocal three-dimensional analysis for the presence of EEC cluster formations.
UNASSIGNED: Examination of multiple areas of macroscopic tumor-free mucosa in surgically resected specimens from patients with familial SI-NET revealed widely distributed, independent, multifocal EEC micro-tumor formations of varying sizes. Consistent with this finding, randomly sampled ileal biopsy specimens identified aberrant crypt containing endocrine cell clusters (ACECs) in patients. ACECs were found exclusively in patients (23/43, 53%) and not in controls (0/20). Furthermore, analysis of positions and numbers of EECs in crypts and ACECs indicated significant increases in EECs at the crypt bottom, predominantly at positions 0 and 1\' (p < 0.0001 compared to controls), suggesting the progression of EEC accumulation below +4 position as the early process of ACEC formation. These findings also suggested that ACECs were precursors in the development of micro-tumors and subsequent macro-tumors.
UNASSIGNED: This study indicates that SI-NETs develop from deep crypt EC cells to become ACECs, micro-tumors, and ultimately gross tumors. This process occurs widely throughout the distal small intestine in patients with familial SI-NETs consistent with but not exclusively explained by germline disease. Finally, analysis of crypts from ileal biopsies could contribute in part to earlier diagnostic screening processes avoiding late-stage presentation of incurable disease.
UNASSIGNED: Isolated crypts from endoscopic ileal biopsies or surgically removed specimens from 43 patients with familial SI-NET and 20 controls were formalin-fixed, immunostained for chromogranin A, and examined by confocal three-dimensional analysis for the presence of EEC cluster formations.
UNASSIGNED: Examination of multiple areas of macroscopic tumor-free mucosa in surgically resected specimens from patients with familial SI-NET revealed widely distributed, independent, multifocal EEC micro-tumor formations of varying sizes. Consistent with this finding, randomly sampled ileal biopsy specimens identified aberrant crypt containing endocrine cell clusters (ACECs) in patients. ACECs were found exclusively in patients (23/43, 53%) and not in controls (0/20). Furthermore, analysis of positions and numbers of EECs in crypts and ACECs indicated significant increases in EECs at the crypt bottom, predominantly at positions 0 and 1\' (p < 0.0001 compared to controls), suggesting the progression of EEC accumulation below +4 position as the early process of ACEC formation. These findings also suggested that ACECs were precursors in the development of micro-tumors and subsequent macro-tumors.
UNASSIGNED: This study indicates that SI-NETs develop from deep crypt EC cells to become ACECs, micro-tumors, and ultimately gross tumors. This process occurs widely throughout the distal small intestine in patients with familial SI-NETs consistent with but not exclusively explained by germline disease. Finally, analysis of crypts from ileal biopsies could contribute in part to earlier diagnostic screening processes avoiding late-stage presentation of incurable disease.
摘要：
未经证实：早期小肠神经内分泌肿瘤（SI-NET）通常无症状且难以诊断。因此,患者常出现晚期不治之症。SI-NET起源于肠嗜铬细胞（EC），在肿瘤进展的早期，在隐窝底部形成由EC细胞亚群组成的肠内分泌细胞（EEC）簇。以家族形式的SI-NET，EEC簇以多焦点和多克隆方式出现。我们试图确定早期发现和分析隐窝EEC簇是否可以深入了解SI-NETs的发展，并成功对SI-NETs患者的有风险家庭成员进行症状前筛查。
UNASSIGNED：对43例家族性SI-NET患者和20例对照患者的内镜回肠活检或手术切除的标本进行福尔马林固定，嗜铬粒蛋白A免疫染色，并通过共聚焦三维分析检查EEC团簇形成的存在。
UNASSIGNED：对家族性SI-NET患者手术切除标本的宏观无瘤粘膜多个区域的检查显示分布广泛，独立,不同大小的多灶性EEC微肿瘤形成。与这一发现一致，随机抽取的回肠活检标本确定了患者中含有内分泌细胞簇（ACEC）的异常隐窝。ACEC仅在患者中发现（23/43，53％），而在对照组中未发现（0/20）。此外，对隐窝和ACEC中EEC的位置和数量的分析表明，隐窝底部的EEC显着增加，主要在位置0和1'（与对照组相比，p<0.0001），提示EEC积累在+4位以下的进展是ACEC形成的早期过程。这些发现还表明，ACEC是微肿瘤和随后的宏观肿瘤发展的前体。
UNASSIGNED：这项研究表明，SI-NET从深隐窝EC细胞发展成为ACEC，微肿瘤，最终是巨大的肿瘤。在家族性SI-NET患者中，该过程广泛发生在整个小肠远端，这与种系疾病一致，但并非仅由种系疾病解释。最后,回肠活检的隐窝分析可部分有助于早期诊断筛查过程,避免晚期出现不治之症.
UNASSIGNED：对43例家族性SI-NET患者和20例对照患者的内镜回肠活检或手术切除的标本进行福尔马林固定，嗜铬粒蛋白A免疫染色，并通过共聚焦三维分析检查EEC团簇形成的存在。
UNASSIGNED：对家族性SI-NET患者手术切除标本的宏观无瘤粘膜多个区域的检查显示分布广泛，独立,不同大小的多灶性EEC微肿瘤形成。与这一发现一致，随机抽取的回肠活检标本确定了患者中含有内分泌细胞簇（ACEC）的异常隐窝。ACEC仅在患者中发现（23/43，53％），而在对照组中未发现（0/20）。此外，对隐窝和ACEC中EEC的位置和数量的分析表明，隐窝底部的EEC显着增加，主要在位置0和1'（与对照组相比，p<0.0001），提示EEC积累在+4位以下的进展是ACEC形成的早期过程。这些发现还表明，ACEC是微肿瘤和随后的宏观肿瘤发展的前体。
UNASSIGNED：这项研究表明，SI-NET从深隐窝EC细胞发展成为ACEC，微肿瘤，最终是巨大的肿瘤。在家族性SI-NET患者中，该过程广泛发生在整个小肠远端，这与种系疾病一致，但并非仅由种系疾病解释。最后,回肠活检的隐窝分析可部分有助于早期诊断筛查过程,避免晚期出现不治之症.
