Department of Pathology, National Taiwan University Hospital.
Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Am J Surg Pathol. 2021 Oct 1;45(10):1409-1418. doi: 10.1097/PAS.0000000000001716.
The molecular characteristics of lymphoepithelioma-like intrahepatic cholangiocarcinoma (LELCC) remain elusive. We examined 27 LELCC cases through next-generation sequencing using a panel of genes commonly mutated in primary liver cancers. Alterations in BAP1, ARID1A, ARID2, and PBRM1 were detected through immunohistochemistry. Fluorescence in situ hybridization was performed to analyze FGFR2 fusions and CCND1 amplification. LELCC is histologically classified as predominantly undifferentiated or glandular. Epstein-Barr virus-encoded small RNA (EBER) expression was found in 16 LELCCs. Approximately 50% of LELCCs expressed programmed death-ligand 1 strongly. Notably, recurrent pTERT and TP53 mutations were detected in 9 (38%) and 8 (33%) tumors, respectively. Only 2 LELCCs exhibited loss of expression for PBRM1. Alterations in genes typically involved in intrahepatic cholangiocarcinoma, including IDH1, IDH2, ARID1A, ARID2, and BAP1, and FGFR2 fusions, were not identified. The 2-step clustering analysis showed 2 distinct subgroups in LELCC, which were separated by EBER expression. A meta-analysis of all reported cases (n=85) has shown that EBER+ LELCC is strongly associated with the female sex, younger age, and exhibited predominantly glandular differentiation (P=0.001, 0.012, and <0.001, respectively). Patients with EBER- LELCC were more likely to have viral hepatitis and cirrhosis (P=0.003 and 0.005, respectively). Genetic analysis demonstrated that EBER- LELCC was significantly associated with pTERT and TP53 mutations (P=0.033 and 0.008, respectively). In conclusion, LELCC is genetically distinct from intrahepatic cholangiocarcinoma. EBER- LELCC may exhibit a different pathogenesis from EBER+ LELCC. High programmed death-ligand 1 expression in LELCC has implications for potential immunotherapeutic strategies.
淋巴上皮样肝内胆管癌（LELCC）的分子特征尚不清楚。我们通过下一代测序使用一组常见于原发性肝癌的基因对 27 例 LELCC 病例进行了检测。通过免疫组织化学检测到 BAP1、ARID1A、ARID2 和 PBRM1 的改变。荧光原位杂交用于分析 FGFR2 融合和 CCND1 扩增。LELCC 在组织学上分为主要未分化或腺状。16 例 LELCC 中发现 Epstein-Barr 病毒编码的小 RNA（EBER）表达。大约 50%的 LELCC 强烈表达程序性死亡配体 1。值得注意的是，分别在 9 例（38%）和 8 例（33%）肿瘤中检测到反复的 pTERT 和 TP53 突变。只有 2 例 LELCC 显示 PBRM1 表达缺失。未发现 IDH1、IDH2、ARID1A、ARID2 和 BAP1 等通常参与肝内胆管癌的基因以及 FGFR2 融合的改变。2 步聚类分析显示 LELCC 有 2 个不同的亚群，通过 EBER 表达来区分。对所有报道病例（n=85）的荟萃分析表明，EBER+ LELCC 与女性、年轻和主要腺状分化密切相关（P=0.001、0.012 和 <0.001）。EBER- LELCC 患者更有可能患有病毒性肝炎和肝硬化（P=0.003 和 0.005）。基因分析表明，EBER- LELCC 与 pTERT 和 TP53 突变显著相关（P=0.033 和 0.008）。总之，LELCC 在遗传上与肝内胆管癌不同。EBER- LELCC 的发病机制可能与 EBER+ LELCC 不同。LELCC 中高程序性死亡配体 1 表达可能对潜在的免疫治疗策略有影响。
