Molecular features of primary hepatic undifferentiated carcinoma

Abstract

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.