Understanding the complexity and heterogeneity of HCC

Abstract

HCC is characterized by considerable morphological, molecular and genetic heterogeneity. Morphological classification based on both gross appearance and histology has been widely used clinically for management and prognostication. The new concept of HCC and CC being ends of a disease spectrum will be discussed. Recently, comprehensive genomic analyses using next-generation sequencing technology has revealed the tumor heterogeneity in HCC consisting of inter-tumoral heterogeneity (including that between patients, found in second primary tumors after curative treatment, and synchronous multifocal tumors of different clonalities) and intra-tumoral heterogeneity (within tumors). The information obtained has been very useful in addressing these issues. Several molecular classifications of human HCCs and HCC classification systems using combined histology and molecular findings have been proposed, e.g. a proliferative and non-proliferative phenotype; but they have not been incorporated into clinical practice. It is also to note that the inter-tumoral heterogeneity poses severe challenges for the development and administration of systemic molecular targeted therapies. On the other hand, intra-tumoral heterogeneity has emerged as a characteristic of tumors, with cancer cells within a tumor displaying distinct differences in properties including growth rate, metastatic capacity, and response to treatment. Substantial inter-tumoral and intra-tumoral heterogeneity renders biomarker identification challenging when applied to a single tumor biopsy specimen. As a future perspective, the use of circulating tumor DNA (ctDNA) to evaluate overall tumor heterogeneity may be an option to help resolve this problem. Studying ctDNA could potentially identify more tumor clones and potentially build up a complete picture of tumor heterogeneity in a longitudinal and dynamic manner.