High-grade neuroendocrine neoplasms (HG-NENs) are clinically aggressive diseases, the classification of which has recently been redefined. They now include both poorly differentiated NENs (neuroendocrine carcinoma, NECs) and high proliferating well-differentiated NENs (called grade 3 neuroendocrine tumors, G3 NETs, in the digestive system). In the last decade, the “molecular revolution” that has affected all fields of medical oncology has also shed light in the understanding of HG NENs heterogeneity and has provided new diagnostic and therapeutic tools, useful in the management of these malignancies. Considering the kaleidoscopic aspects of HG NENs in various anatomical sites, this review systematically addresses the genomic landscape of such neoplasm throughout the more common thoracic and digestive locations, as well as it will consider other rare but not exceptional primary sites, including the skin, the head and neck, and the urogenital system. The revision of the available literature will then be oriented to understand the translational relevance of molecular data, by analyzing conceptual issues, clinicopathological correlations, and unmet needs in this field.

高级别神经内分泌肿瘤 (HG-NEN) 是临床上具有侵袭性的疾病，最近对其分类进行了重新定义。它们现在包括低分化的 NEN（神经内分泌癌，NEC）和高增殖的高分化 NEN（在消化系统中称为 3 级神经内分泌肿瘤，G3 NET）。在过去十年中，影响医学肿瘤学所有领域的“分子革命”也阐明了对 HG NENs 异质性的理解，并提供了新的诊断和治疗工具，可用于管理这些恶性肿瘤。考虑到 HG NEN 在不同解剖部位的千变万化的方面，本综述系统地解决了这种肿瘤在更常见的胸部和消化部位的基因组景观，还将考虑其他罕见但并非特殊的原发部位，包括皮肤、头颈部和泌尿生殖系统。然后，通过分析该领域的概念问题、临床病理学相关性和未满足的需求，对现有文献的修订将旨在了解分子数据的转化相关性。