Neuroendocrine tumors (NETs) are often diagnosed from the metastases of an unknown primary tumor. Specific immunohistochemical (IHC) markers indicating the location of a primary tumor are needed. The proprotein convertase subtilisin/kexin type 2 (PCSK2) is found in normal neural and neuroendocrine cells, and known to express in NETs. We investigated the tissue microarray (TMA) of 86 primary tumors from 13 different organs and 9 metastatic NETs, including primary tumor‐metastasis pairs, for PCSK2 expression with polymer‐based IHC. PCSK2 was strongly positive in all small intestine and appendiceal NETs, the so‐called midgut NETs, in most pheochromocytomas and paragangliomas, and in some of the typical and atypical pulmonary carcinoid tumors. NETs showing strong positivity were re‐evaluated in larger tumor cohorts confirming the primary observation. In the metastases, the expression of PCSK2 mirrored that of the corresponding primary tumors. We found negative or weak staining in NETs from the thymus, gastric mucosa, pancreas, rectum, thyroid, and parathyroid. PCSK2 expression did not correlate with Ki‐67 in well‐differentiated NETs. Our data suggest that PCSK2 positivity can indicate the location of the primary tumor. Thus, PCSK2 could function in the IHC panel determined from screening metastatic NET biopsies of unknown primary origins.

中文翻译：

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神经内分泌肿瘤中PCSK2的表达指向中肠，肺或嗜铬细胞瘤-副神经节瘤起源。

神经内分泌肿瘤（NETs）通常是从未知原发肿瘤的转移灶中诊断出来的。需要指示原发肿瘤位置的特异性免疫组化（IHC）标记。在正常的神经和神经内分泌细胞中发现了前蛋白转化酶枯草杆菌蛋白酶/ kexin 2型（PCSK2），已知在NETs中表达。我们调查了来自13个不同器官和9个转移性NET的86种原发性肿瘤的组织微阵列（TMA），以基于聚合物的IHC进行PCSK2表达。PCSK2在所有小肠和阑尾网（所谓的中肠网），大多数嗜铬细胞瘤和副神经节瘤以及某些典型和非典型的肺类癌瘤中均呈强阳性。在较大的肿瘤队列中重新评估了显示强阳性的NET，从而证实了主要观察结果。在转移中，PCSK2的表达与相应原发性肿瘤的表达相似。我们发现胸腺，胃黏膜，胰腺，直肠，甲状腺和甲状旁腺的NET染色呈阴性或弱染色。在分化良好的NETs中，PCSK2表达与Ki-67不相关。我们的数据表明PCSK2阳性可以指示原发肿瘤的位置。因此，PCSK2可以在IHC小组中发挥作用，该小组通过筛查未知来源的转移性NET活检确定。我们的数据表明PCSK2阳性可以指示原发肿瘤的位置。因此，PCSK2可以在IHC小组中发挥作用，该小组通过筛查未知来源的转移性NET活组织检查确定。我们的数据表明PCSK2阳性可以指示原发肿瘤的位置。因此，PCSK2可以在IHC小组中发挥作用，该小组通过筛查未知来源的转移性NET活检确定。