Abstract：
In this review, we detail the changes and the relevant features that are applied to neuroendocrine neoplasms (NENs) in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors. Using a question-and-answer approach, we discuss the consolidation of the nomenclature that distinguishes neuronal paragangliomas from epithelial neoplasms, which are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The criteria for these distinctions based on differentiation are outlined. NETs are generally (but not always) graded as G1, G2, and G3 based on proliferation, whereas NECs are by definition high grade; the importance of Ki67 as a tool for classification and grading is emphasized. The clinical relevance of proper classification is explained, and the importance of hormonal function is examined, including eutopic and ectopic hormone production. The tools available to pathologists for accurate classification include the conventional biomarkers of neuroendocrine lineage and differentiation, INSM1, synaptophysin, chromogranins, and somatostatin receptors (SSTRs), but also include transcription factors that can identify the site of origin of a metastatic lesion of unknown primary site, as well as hormones, enzymes, and keratins that play a role in functional and structural correlation. The recognition of highly proliferative, well-differentiated NETs has resulted in the need for biomarkers that can distinguish these G3 NETs from NECs, including stains to determine expression of SSTRs and those that can indicate the unique molecular pathogenetic alterations that underlie the distinction, for example, global loss of RB and aberrant p53 in pancreatic NECs compared with loss of ATRX, DAXX, and menin in pancreatic NETs. Other differential diagnoses are discussed with recommendations for biomarkers that can assist in correct classification, including the distinctions between epithelial and non-epithelial NENs that have allowed reclassification of epithelial NETs in the spine, in the duodenum, and in the middle ear; the first two may be composite tumors with neuronal and glial elements, and as this feature is integral to the duodenal lesion, it is now classified as composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). The many other aspects of differential diagnosis are detailed with recommendations for biomarkers that can distinguish NENs from non-neuroendocrine lesions that can mimic their morphology. The concepts of mixed neuroendocrine and non-neuroendocrine (MiNEN) and amphicrine tumors are clarified with information about how to approach such lesions in routine practice. Theranostic biomarkers that assist patient management are reviewed. Given the significant proportion of NENs that are associated with germline mutations that predispose to this disease, we explain the role of the pathologist in identifying precursor lesions and applying molecular immunohistochemistry to guide genetic testing.
摘要：
在这次审查中,我们详细介绍了2022年WHO内分泌和神经内分泌肿瘤分类中应用于神经内分泌肿瘤(NENs)的变化和相关特征.使用问答方法，我们讨论区分神经元副神经节瘤和上皮肿瘤的命名法的巩固，分为高分化神经内分泌肿瘤（NETs）和低分化神经内分泌癌（NECs）。概述了基于区分的这些区别的标准。根据增殖，NETs通常(但不总是)分级为G1、G2和G3，而根据定义，NEC是高等级的；强调了Ki67作为分类和分级工具的重要性。解释了正确分类的临床相关性，检查荷尔蒙功能的重要性，包括异位和异位激素的产生。病理学家可用于准确分类的工具包括神经内分泌谱系和分化的常规生物标志物。INSM1，突触素，嗜铬粒蛋白,和生长抑素受体（SSTR），但也包括转录因子，可以识别未知原发部位的转移灶的起源部位，以及荷尔蒙，酶，和角蛋白在功能和结构相关中起作用。高度增殖的识别，分化良好的NETs导致了对可以区分这些G3NETs和NECs的生物标志物的需求，包括确定SSTR表达的染色剂，以及那些可以表明独特的分子致病改变的区别，例如,胰腺NEC中RB和异常p53的整体丢失与ATRX的丢失相比，DAXX,和胰腺NETs中的脑膜。讨论了其他鉴别诊断，并推荐了可以帮助正确分类的生物标志物。包括允许脊柱上皮NETs重新分类的上皮和非上皮NENs之间的区别，在十二指肠，在中耳；前两个可能是神经元和神经胶质成分的复合肿瘤，由于这个特征是十二指肠病变不可或缺的，它现在被分类为复合神经节细胞瘤/神经瘤和神经内分泌肿瘤（CoGNET）。鉴别诊断的许多其他方面都详细介绍了生物标志物的建议，这些生物标志物可以区分NEN和可以模拟其形态的非神经内分泌病变。通过有关如何在常规实践中处理此类病变的信息，阐明了混合神经内分泌和非神经内分泌（MiNEN）和苯丙胺肿瘤的概念。回顾了协助患者管理的Theranostic生物标志物。考虑到与易患这种疾病的种系突变相关的NENs的显著比例，我们解释了病理学家在识别前体病变和应用分子免疫组织化学指导基因检测方面的作用。
