Tumor Heterogeneity in Hepatocellular Carcinoma: Facing the Challenges

Abstract

Tumor heterogeneity in hepatocellular carcinoma (HCC), such as that found in second primary tumors after curative treatment, synchronous multifocal tumors of different clonality, or intratumor heterogeneity, poses severe challenges for the development and administration of systemic molecular targeted therapies. Various methodologies, including historical DNA ploidy analysis, integrated hepatitis B virus DNA analysis, DNA fingerprinting, and next-generation sequencing technologies, are used to explore tumor heterogeneity in HCC. It is estimated that 30%-60% of recurrent or metastatic tumors harbor clones different from the primary tumor, 22%-79% of synchronous tumors vary clonally, and 12%-66% of single tumors contain intratumor heterogeneity. Substantial intertumor and intratumor heterogeneity renders biomarker identification, which is critical for the development and administration of molecular targeted therapy, challenging when applied to a single tumor biopsy specimen. The use of circulating tumor cells or circulating tumor DNA to evaluate overall tumor heterogeneity may help resolve this problem. This article reviews previous studies of tumor heterogeneity and discusses the implications and future opportunities regarding tumor heterogeneity in HCC.

Keywords: Circulating tumor DNA; Circulating tumor cell; Clonality; Hepatocellular carcinoma; Tumor heterogeneity.

Fig. 1

Tumor heterogeneity of HCC. a Recurrent HCC after hepatic resection may arise from intrahepatic metastasis of the primary tumor or may be a second de novo primary tumor. b Multiple HCCs may occur multicentrically (intertumor heterogeneity) or may arise from intrahepatic metastasis. c Intratumor heterogeneity may arise from a dedifferentiation process (nodule-in-nodule appearance, left) or be clonal evolution within a single HCC tumor (right).