Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Mod Pathol. 2022 May;35(5):680-687. doi: 10.1038/s41379-021-00970-z. Epub 2021 Dec 23.
The clinicopathological and molecular characteristics of primary hepatic undifferentiated carcinoma are poorly defined. It is speculated that primary hepatic undifferentiated carcinoma develops in the setting of preceding primary hepatic carcinoma. We investigated 14 primary hepatic undifferentiated carcinomas through targeted next-generation sequencing and immunohistochemistry. A panel of genes commonly mutated in primary liver carcinomas were examined. We found a similar clinical context as primary hepatic carcinoma, including a high prevalence of chronic viral hepatitis (86%), cirrhosis (57%), and elevated alpha-fetoprotein (29%). Tumors had sheet-like and poorly cohesive growth patterns. Rhabdoid cytomorphology was observed in four samples. Notably, the most common genetic mutations in primary hepatic undifferentiated carcinoma were in the promoter of TERT (n = 8, 57%) and TP53 (n = 8, 57%), which are common in hepatocellular carcinoma. The mutation rate of TP53 was elevated compared with hepatocellular carcinoma. No other typical genetic features of intrahepatic cholangiocarcinoma were identified, such as an IDH1/IDH2 mutation, FGFR2 fusions, or aberrant BAP1 expression. Furthermore, novel switch/sucrose nonfermenting complex inactivation was found, including SMARCA4/SMARCA2 (n = 1) and PBRM1 deficiency (n = 2). The three tumors demonstrated poorly cohesive histology, including rhabdoid features. High PD-L1 expression (57%) was observed in a majority of the tumors. Primary hepatic undifferentiated carcinoma shares clinical and genetic features with hepatocellular carcinoma but harbors progressive molecular characteristics that may initiate tumor dedifferentation. High PD-L1 expression in primary hepatic undifferentiated carcinoma may be a useful biomarker for potential immunotherapeutic strategies.
原发性肝未分化癌的临床病理和分子特征定义不明确。据推测，原发性肝未分化癌是在前原发性肝癌的基础上发展而来的。我们通过靶向下一代测序和免疫组织化学研究了 14 例原发性肝未分化癌。检查了一组常见于原发性肝癌的基因突变。我们发现了与原发性肝癌相似的临床背景，包括慢性病毒性肝炎（86%）、肝硬化（57%）和甲胎蛋白升高（29%）的高发率。肿瘤具有片状和非黏附性生长模式。四个样本中观察到横纹肌样细胞形态。值得注意的是，原发性肝未分化癌中最常见的基因突变是 TERT（n=8，57%）和 TP53（n=8，57%）启动子的突变，这在肝细胞癌中很常见。TP53 的突变率高于肝细胞癌。未发现肝内胆管癌的其他典型遗传特征，如 IDH1/IDH2 突变、FGFR2 融合或异常 BAP1 表达。此外，还发现了新的开关/蔗糖非发酵复合物失活，包括 SMARCA4/SMARCA2（n=1）和 PBRM1 缺失（n=2）。这三个肿瘤表现出非黏附性组织学特征，包括横纹肌样特征。大多数肿瘤中观察到 PD-L1 高表达（57%）。原发性肝未分化癌与肝细胞癌具有相似的临床和遗传特征，但具有潜在的肿瘤去分化的进展性分子特征。原发性肝未分化癌中高 PD-L1 表达可能是潜在免疫治疗策略的有用生物标志物。
