Benini L, Gervaso L, Frassoni S, Bagnardi V, Cella C A, Algeri L, Ciardiello D, Zampino M G, Winchler C, Boselli S, Tamayo D, Spada F, Fazio N
Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy.
Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy.
J Neuroendocrinol. 2025 Sep;37(9):e70057. doi: 10.1111/jne.70057. Epub 2025 Jun 18.
Poorly differentiated neuroendocrine carcinomas (NECs) are rare malignancies with a dismal prognosis, few therapeutic options, and a lack of predictive factors. We describe a large series of extra-pulmonary (EP) NEC patients from a neuroendocrine neoplasm (NEN) referral center, aiming to improve the clinical management of these diseases. Medical records of patients with histological diagnosis of pure histology EP-NEC, discussed at the NEN-dedicated multidisciplinary team (MDT) between October 2018 and August 2022, were included. Demographic features, tumor characteristics, molecular profile, treatments, and responses to treatments were collected. Among 1594 NEN diagnoses discussed at the MDT during the study period, 377 were NECs; the final population consisted of 173 patients, mostly presenting with advanced disease and often with a gastroenteropancreatic tract primary tumor. Molecular profiling was available for 52 patients (30%). The most frequent alterations occurred in TP53 and KRAS. One of 25 patients tested for microsatellite instability was confirmed MSI-h; one of 52 patients tested had a high tumor mutational burden (TMB = 19). Median overall survival (OS) was 15.4 months (95% confidence interval [CI]: 13.2-18.5). Most patients with advanced disease received a first-line chemotherapy (136/153 [88.9%]), often platinum plus etoposide (111/136 patients [82%]). The overall response rate (ORR) to first-line was 40%. Median progression-free survival (PFS) was 5.7 months (95% CI: 4.4-6.4). Forty-two percent and 18% of patients received second- and third-line therapy, respectively. No significant difference was seen when stratifying OS and PFS by Ki-67 groups and tumor cell morphology, whereas performance status and presence of metastases were significantly related to OS. In this single-center retrospective large series of EP-NECs, almost half of the patients showed a tumor response to first-line chemotherapy. No relevant correlation was found with primary site, tumor cell morphology, or Ki-67. The proportion of patients receiving subsequent lines, along with the mOS, confirms the aggressiveness of this disease. Molecular profiling was performed only fragmentarily, with limited practical applicability. Efforts shall be made in the future to implement these investigations.
低分化神经内分泌癌（NEC）是一种罕见的恶性肿瘤，预后不良，治疗选择有限，且缺乏预测因素。我们描述了来自一个神经内分泌肿瘤（NEN）转诊中心的大量肺外（EP）NEC患者系列，旨在改善这些疾病的临床管理。纳入了2018年10月至2022年8月期间在NEN专门的多学科团队（MDT）讨论过的组织学诊断为纯组织学EP-NEC患者的病历。收集了人口统计学特征、肿瘤特征、分子谱、治疗方法及治疗反应。在研究期间MDT讨论的1594例NEN诊断中，377例为NEC；最终纳入173例患者，大多表现为晚期疾病，且常以胃肠胰道为原发肿瘤。52例患者（30%）有分子谱数据。最常见的改变发生在TP53和KRAS基因。25例检测微卫星不稳定性的患者中有1例被确认为微卫星高度不稳定（MSI-h）；52例检测的患者中有1例肿瘤突变负荷高（TMB = 19）。中位总生存期（OS）为15.4个月（95%置信区间[CI]：13.2 - 18.5）。大多数晚期患者接受了一线化疗（136/153 [88.9%]），常采用铂类加依托泊苷（111/136例患者[82%]）。一线治疗的总缓解率（ORR）为40%。中位无进展生存期（PFS）为5.7个月（95% CI：4.4 - 6.4）。分别有42%和18%的患者接受了二线和三线治疗。按Ki-67分组和肿瘤细胞形态对OS和PFS进行分层时未发现显著差异，而体能状态和转移的存在与OS显著相关。在这个单中心回顾性大样本EP-NEC系列中，近一半的患者对一线化疗有肿瘤反应。未发现与原发部位、肿瘤细胞形态或Ki-67有相关关联。接受后续治疗线的患者比例以及中位总生存期证实了这种疾病的侵袭性。分子谱分析仅部分进行，实际应用有限。未来应努力开展这些研究。
