Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori (IRST) IRCCS, Meldola, Italy.
Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy.
Endocr Pathol. 2021 Jun;32(2):309-317. doi: 10.1007/s12022-020-09657-8. Epub 2021 Jan 6.
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare and heterogeneous subgroup of tumors with a challenging management because of their extremely variable biological and clinical behaviors. Due to their different prognosis, there is an urgent need to identify molecular markers which would enable to discriminate between grade 3 neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), despite both being diagnosed mainly on the basis of proliferation index and cell differentiation. DLL3, a negative Notch regulator, is a promising molecular target highly expressed in several tumors with neuroendocrine features. We conducted a retrospective analysis of DLL3, RB1, and PD-L1 expression by immunohistochemistry (IHC), in formalin-fixed, paraffin-embedded (FFPE) samples from 47 patients with GEP-NENs. Then, we correlated the results with patients' clinical features and outcome. The absence of DLL3 expression in 5 well-differentiated GEP-NETs with high-grade features (G3 NET), and the presence of DLL3 in 76.9% of poorly-differentiated NECs (G3 NEC), highlights DLL3 expression as a marker of G3 NECs (p = 0.007). DLL3 expression was correlated with RB1-loss (p < 0.001), negative Ga-PET/CT scan (p = 0.001), and an unfavorable clinical outcome, with important implications for treatment response and patient's follow-up. Median progression-free survival (PFS) and overall survival (OS) were 22.7 months (95% CI 6.1-68.8) and 68.8 months (95% CI 26.0-78.1), respectively, in patients with DLL3-negative tumor compared with 5.2 months (95% CI 2.5-18.5) and 9.5 months (95% CI 2.5-25.2), respectively, in patients with DLL3-positive tumor (PFS p = 0.0083, OS p = 0.0071). Therefore, combined with morphological cell analysis, DLL3 could represent a valuable histological marker, for the diagnosis of poorly differentiated NECs. The high percentage of DLL3 expression in NEC patients also highlights a potential opportunity for a DLL3 targeted therapy in this tumor subset.
胃肠胰神经内分泌肿瘤（GEP-NENs）是一组罕见且异质性的肿瘤亚群，由于其生物学和临床行为极其多样化，因此具有挑战性的管理。由于其预后不同，因此迫切需要识别分子标志物，以便能够区分 3 级神经内分泌肿瘤（NETs）和神经内分泌癌（NECs），尽管这两种肿瘤主要都是基于增殖指数和细胞分化来诊断的。DLL3 是一种负性 Notch 调节剂，是一种很有前途的分子靶标，在具有神经内分泌特征的几种肿瘤中高表达。我们对 47 例 GEP-NENs 的福尔马林固定、石蜡包埋（FFPE）样本进行了 DLL3、RB1 和 PD-L1 的免疫组织化学（IHC）表达的回顾性分析，然后将结果与患者的临床特征和结果相关联。在 5 例具有高级别特征的分化良好的 GEP-NETs（G3 NET）中缺乏 DLL3 表达，而在 76.9%的低分化 NECs（G3 NEC）中存在 DLL3 表达，这突出了 DLL3 表达作为 G3 NEC 标志物的重要性（p=0.007）。DLL3 表达与 RB1 缺失（p<0.001）、负 Ga-PET/CT 扫描（p=0.001）和不利的临床结果相关，对治疗反应和患者随访具有重要意义。与 DLL3 阴性肿瘤患者的中位无进展生存期（PFS）和总生存期（OS）分别为 22.7 个月（95%CI 6.1-68.8）和 68.8 个月（95%CI 26.0-78.1）相比，DLL3 阳性肿瘤患者的中位 PFS 和 OS 分别为 5.2 个月（95%CI 2.5-18.5）和 9.5 个月（95%CI 2.5-25.2）（PFS p=0.0083，OS p=0.0071）。因此，结合形态学细胞分析，DLL3 可能成为诊断低分化 NEC 的有价值的组织学标志物。NEC 患者中 DLL3 表达的高比例也突出了 DLL3 靶向治疗在该肿瘤亚群中的潜在机会。
