Tang Hui, Jiang Xiaojun, Zhu Lili, Xu Liming, Wang Xiaoxi, Li Hong, Gao Feifei, Liu Xinxin, Ren Chuanli, Zhao Yan
Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Hepatobiliary and Pancreatic Surgery, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Histol Histopathol. 2025 Mar;40(3):389-400. doi: 10.14670/HH-18-788. Epub 2024 Jul 2.
Gallbladder neuroendocrine carcinomas (GB-NECs) are a rare subtype of malignant gallbladder cancer (GBC). The genetic and molecular characteristics of GB-NECs are rarely reported. This study aims to assess the frequency of microsatellite instability (MSI) in GB-NECs and characterize their clinicopathologic and molecular features in comparison with gallbladder adenocarcinomas (GB-ADCs). Data from six patients with primary GB-NECs and 13 with GB-ADCs were collected and reevaluated. MSI assay, immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2), comprehensive genomic profiling (CGP) via next-generation sequencing (NGS), and evaluation of tumor mutation burden (TMB) were conducted on these samples. The six GB-NEC cases were all female, with a mean age of 62.0±9.2 years. Of these, two cases were diagnosed as large cell neuroendocrine carcinomas (LCNECs), while the remaining four were small cell neuroendocrine carcinomas (SCNECs). Microsatellite states observed in both GB-NECs and GB-ADCs were consistently microsatellite stable (MSS). Notably, (100%, 6/6) and (100%, 6/6) exhibited the highest mutation frequency in GB-NECs, followed by (50%, 3/6), (50%, 3/6), and (33%, 2/6), with and specifically present in GB-NECs. Immunohistochemical (IHC) assays of p53 and Rb in the six GB-NECs were highly consistent with genetic mutations detected by targeted NGS. Moreover, no statistical difference was observed in TMB between GB-NECs and GB-ADCs (=0.864). Although overall survival in GB-NEC patients tended to be worse than in GB-ADC patients, this difference did not reach statistical significance (=0.119). This study has identified the microsatellite states and molecular mutation features of GB-NECs, suggesting that co-mutations in and may signify a neuroendocrine inclination in GB-NECs. The IHC assay provides an effective complement to targeted NGS for determining the functional status of p53 and Rb in clinical practice.
胆囊神经内分泌癌（GB-NECs）是恶性胆囊癌（GBC）的一种罕见亚型。GB-NECs的遗传和分子特征鲜有报道。本研究旨在评估GB-NECs中微卫星不稳定性（MSI）的频率，并与胆囊腺癌（GB-ADCs）比较，以表征其临床病理和分子特征。收集并重新评估了6例原发性GB-NECs患者和13例GB-ADCs患者的数据。对这些样本进行了MSI检测、错配修复蛋白（MLH1、MSH2、MSH6和PMS2）的免疫组织化学检测、通过下一代测序（NGS）进行的综合基因组分析（CGP）以及肿瘤突变负荷（TMB）评估。6例GB-NECs病例均为女性，平均年龄62.0±9.2岁。其中，2例被诊断为大细胞神经内分泌癌（LCNECs），其余4例为小细胞神经内分泌癌（SCNECs）。在GB-NECs和GB-ADCs中观察到的微卫星状态均为微卫星稳定（MSS）。值得注意的是，（100%，6/6）和（100%，6/6）在GB-NECs中表现出最高的突变频率，其次是（50%，3/6）、（50%，3/6）和（33%，2/6），其中和特别存在于GB-NECs中。6例GB-NECs中p53和Rb的免疫组织化学（IHC）检测结果与靶向NGS检测到的基因突变高度一致。此外，GB-NECs和GB-ADCs之间的TMB没有统计学差异（=0.864）。虽然GB-NEC患者的总生存期往往比GB-ADC患者差，但这种差异未达到统计学意义（=0.119）。本研究确定了GB-NECs的微卫星状态和分子突变特征，表明和中的共突变可能表明GB-NECs具有神经内分泌倾向。IHC检测为在临床实践中确定p53和Rb的功能状态提供了对靶向NGS的有效补充。
