Prisciandaro Michele, Antista Maria, Raimondi Alessandra, Corti Francesca, Morano Federica, Centonze Giovanni, Sabella Giovanna, Mangogna Alessandro, Randon Giovanni, Pagani Filippo, Prinzi Natalie, Niger Monica, Corallo Salvatore, Castiglioni di Caronno Erica, Massafra Marco, Bartolomeo Maria Di, de Braud Filippo, Milione Massimo, Pusceddu Sara
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
Front Oncol. 2022 Feb 4;12:780716. doi: 10.3389/fonc.2022.780716. eCollection 2022.
Neuroendocrine tumors (NETs) are classified based on morphology and are graded based on their proliferation rate as either well-differentiated low-grade (G1) to intermediate (G2-G3) or poorly differentiated high-grade neuroendocrine carcinomas (NEC G3). Recently, in gastroenteropancreatic (GEP) NETs, a new subgroup of well-differentiated high-grade tumors (NET G3) has been divided from NEC by WHO due to its different clinical-pathologic features. Although several mutational analyses have been performed, a molecular classification of NET is an unmet need in particular for G3, which tends to be more aggressive and have less benefit to the available therapies. Specifically, new possible prognostic and, above all, predictive factors are highly awaited, giving the basis for new treatments. Alteration of , , and is mainly reported, but also druggable alterations, including and high microsatellite instability (MSI-H), have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. In this review, we describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting.
神经内分泌肿瘤（NETs）根据形态学进行分类，并根据其增殖率分为高分化低级别（G1）至中级别（G2 - G3），或低分化高级别神经内分泌癌（NEC G3）。最近，在胃肠胰（GEP）NETs中，由于其不同的临床病理特征，世界卫生组织（WHO）从NEC中划分出了一个新的高分化高级别肿瘤亚组（NET G3）。尽管已经进行了多项突变分析，但NET的分子分类仍然是一个未满足的需求，特别是对于G3而言，G3往往更具侵袭性，且对现有治疗的获益较少。具体而言，人们迫切期待新的可能的预后因素，尤其是预测因素，为新的治疗提供依据。主要报道了 、 和 的改变，但在部分患者亚组中也记录了可靶向治疗的改变，包括 和高微卫星不稳定性（MSI - H）。此外，PD - L1在G3 NETs中高度表达，可能成为鉴别G3神经内分泌肿瘤（NEN）的新生物标志物以及免疫治疗反应的预测标志物。在本综述中，我们描述了关于高级别NET分子格局的现有知识，特别关注那些在晚期具有潜在治疗靶点的情况。
