Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Drum Tower Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu Province, China.
Department of Medical Imaging, The Affiliated Suqian First People's Hospital of Nanjing Medical University, 223800, Suqian, Jiangsu Province, China.
J Cancer Res Clin Oncol. 2024 Aug 28;150(8):403. doi: 10.1007/s00432-024-05894-0.
This study aimed to establish a uniform standard for the interpretation of HER2 gene and protein statuses in intrahepatic cholangiocarcinoma (ICC). We also intended to explore the clinical pathological characteristics, molecular features, RNA expression and immune microenvironment of HER2-positive ICC.
We analyzed a cohort of 304 ICCs using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) to identify HER2 status. Comprehensive analyses of the clinicopathological, molecular genetic, and RNA expression characterizations of ICCs with varying HER2 statuses were performed using next-generation sequencing. We further investigated the tumor microenvironment of ICCs with different HER2 statuses using IHC and multiplex immunofluorescence staining.
HER2/CEP17 ratio of ≥ 2.0 and HER2 copy number ≥ 4.0; or HER2 copy number ≥ 6.0 were setup as FISH positive criteria. Based on this criterion, 13 (4.27%, 13/304) samples were classified as having HER2 amplification. The agreement between FISH and IHC results in ICC was poor. HER2-amplified cases demonstrated a higher tumor mutational burden compared to non-amplified cases. No significant differences were observed in immune markers between the two groups. However, an increased density of CD8 + CTLA4 + and CD8 + FOXP3 + cells was identified in HER2 gene-amplified cases.
FISH proves to be more appropriate as the gold standard for HER2 evaluation in ICC. HER2 gene-amplified ICCs exhibit poorer prognosis, higher mutational burden, and T cell exhaustion and immune suppressed microenvironment.
本研究旨在建立一种统一的标准来解释肝内胆管癌（ICC）中 HER2 基因和蛋白状态。我们还旨在探索 HER2 阳性 ICC 的临床病理特征、分子特征、RNA 表达和免疫微环境。
我们使用免疫组织化学（IHC）和荧光原位杂交（FISH）分析了 304 例 ICC 病例，以确定 HER2 状态。使用下一代测序对具有不同 HER2 状态的 ICC 进行了综合的临床病理、分子遗传和 RNA 表达特征分析。我们还使用 IHC 和多重免疫荧光染色进一步研究了具有不同 HER2 状态的 ICC 的肿瘤微环境。
HER2/CEP17 比值≥2.0 和 HER2 拷贝数≥4.0；或 HER2 拷贝数≥6.0 被设定为 FISH 阳性标准。根据该标准，13（4.27%，13/304）例样本被归类为 HER2 扩增。ICC 中 FISH 和 IHC 结果之间的一致性较差。与非扩增病例相比，HER2 扩增病例的肿瘤突变负担更高。两组之间的免疫标志物没有显著差异。然而，在 HER2 基因扩增病例中，CD8+CTLA4+和 CD8+FOXP3+细胞的密度增加。
FISH 被证明是评估 ICC 中 HER2 的更合适的金标准。HER2 基因扩增的 ICC 预后较差，突变负担较高，T 细胞耗竭和免疫抑制微环境。
