Neuroendocrine neoplasms (NENs) have traditionally been identified via expression of proteins associated to the regulation of secretory vesicles and granules. We report the clinical usage of the “second-generation” proteins ISL LIM homeobox 1 (ISL1), INSM transcriptional repressor 1 (INSM1), and secretagogin (SECG) as immunohistochemical markers of neuroendocrine differentiation since their introduction in clinical routine and compare the results with the established proteins chromogranin A (CGA) and synaptophysin (SYP). In total, 161 tumors, including 139 NENs and 22 “non-NENs” (unrelated tumors with an initial suspicion of NEN), were informatively stained for ISL1, and subsets were also interrogated for INSM1 and/or SECG. Diffuse or focal positive immunoreactivity was noted for ISL1 in 91/139 NENs (65%) and in 6/22 (27%) non-NENs, for INSM1 in 76/85 NENs (89%) and in 2/5 (40%) non-NENs, and for SECG in 49 out of 64 NENs (77%) and in 0/5 non-NENs (0%). Generally, ISL1, INSM1, and SECG exhibited sensitivities in line with or slightly below that of CGA and SYP—largely attributable to tissue-specific patterns regarding tumoral origin. Moreover, for pancreatic and small intestinal NENs, the two largest subgroups, ISL1 staining results were consistent irrespectively of tumor source and WHO grade. We verify previously suggested immunohistochemical schemes of neuroendocrine markers of first- and second-generations to facilitate the diagnostic process for NENs and confirm that the second-generation neuroendocrine markers display tissue-specific patterns. We therefore recommend their implementation in tertiary endocrine pathology centers, not least to aid in the identification of primary tumors when analyzing metastases.

神经内分泌肿瘤 (NEN) 传统上是通过表达与分泌囊泡和颗粒调节相关的蛋白质来鉴定的。我们报告了“第二代”蛋白质 ISL LIM 同源框 1 (ISL1)、INSM 转录抑制因子 1 (INSM1) 和促分泌素 (SECG) 作为神经内分泌分化的免疫组织化学标志物的临床用途，因为它们被引入临床常规并比较结果与已建立的蛋白质嗜铬粒蛋白 A (CGA) 和突触素 (SYP)。总共有 161 个肿瘤，包括 139 个 NEN 和 22 个“非 NEN”（最初怀疑为 NEN 的无关肿瘤），对 ISL1 进行了信息性染色，并且还询问了亚组的 INSM1 和/或 SECG。在 91/139 NEN (65%) 和 6/22 (27%) 非 NEN 中发现 ISL1 的弥漫性或局灶性阳性免疫反应性，76/85 NEN (89%) 和 2/5 (40%) 非 NEN 中的 INSM1，64 个 NEN 中的 49 个 (77%) 和 0/5 非 NEN (0%) 中的 SECG。一般来说，ISL1、INSM1 和 SECG 表现出的敏感性与 CGA 和 SYP 一致或略低于其——主要归因于关于肿瘤起源的组织特异性模式。此外，对于胰腺和小肠 NENs，两个最大的亚组，ISL1 染色结果是一致的，无论肿瘤来源和 WHO 分级如何。我们验证了先前建议的第一代和第二代神经内分泌标志物的免疫组织化学方案，以促进 NEN 的诊断过程，并确认第二代神经内分泌标志物显示组织特异性模式。因此，我们建议在三级内分泌病理中心实施，