Diagnostic value of whole-mount crypt analysis of ileal biopsy specimens for the patients with familial small intestinal neuroendocrine tumors.
Diagnostic value of whole-mount crypt analysis of ileal biopsy specimens for the patients with familial small intestinal neuroendocrine tumors.
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DOI：
10.1177/17588359231156871
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发表时间：
2023
影响因子：
4.9
通讯作者：
Wank, Stephen A.
中科院分区：
文献类型：
--
作者：
Sei, Yoshitatsu;Forbes, Joanne;Da, Ben;Chitsaz, Ehsan;Feng, Jianying;Zhao, Xilin;Hughes, Marybeth S.;Wank, Stephen A.
早期小肠神经内分泌肿瘤(SI-NETs)一般无症状，诊断困难。因此，患者往往出现晚期不治之症。SI-Nets起源于肠嗜铬细胞(EC)，在肿瘤进展的早期阶段，它在隐窝底部形成由EC细胞亚群组成的肠内分泌细胞(EEC)簇。在SI-Net的家族形式中，EEC簇以多焦点和多克隆的方式出现。我们试图确定早期发现和分析隐匿性EEC簇是否可以深入了解SI-Net的发展，并允许对SI-Net患者的高危家庭成员进行成功的症状前筛查。从43例家族性SI-Net患者和20例对照组的内窥镜活检或手术切除标本中分离的隐窝经福尔马林固定，嗜铬粒蛋白A免疫组织化学染色，并通过共聚焦三维分析检查EEC簇的存在。对来自家族性SI-Net患者的手术切除标本的多个区域的宏观无肿瘤粘膜的检查显示，广泛分布的、独立的、多灶性的、大小不一的EEC微肿瘤形成。与这一发现一致的是，随机抽样的回肠活检样本在患者中发现了含有内分泌细胞团(ACECs)的异常隐窝。ACEC仅见于患者(23/43，53%)，对照组未见(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显著增加，主要是在0和1‘位置(p <； 0.0001与对照组相比)，这表明EEC在+4位置以下的积聚是ACEC形成的早期过程。这些发现也提示ACEC是微小肿瘤和随后的大肿瘤发生的前驱细胞。这项研究表明，SI-Net从深隐窝EC细胞发展为血管内皮细胞、微小肿瘤，并最终发展为大体肿瘤。这一过程广泛发生在家族性SI-Net患者的整个小肠末端，这与生殖系疾病一致，但不是唯一的解释。最后，回肠活检隐窝的分析可以部分有助于早期诊断筛查过程，避免晚期不治之症的出现。
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. 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. 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. 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.
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影响因子：
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