Understanding the complexity and heterogeneity of HCC (morphology, molecular and genomic) and its challenges

Abstract

Hepatocellular carcinoma (HCC) is characterized by considerable morphological, molecular and genetic heterogeneity. Discussion in this presentation will focus on all these aspects to address HCC heterogeneity comprehensively. HCC heterogeneity consists 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 same tumors). Morphological classification based on both gross appearance and histology has long been widely used clinically for management and prognostication. The new WHO classification of HCC and the concept of HCC and CC being ends of a disease spectrum will be highlighted in this presentation. Several HCC classification systems using combined histology and molecular findings have been proposed, e.g. a proliferative and non-proliferative phenotype; but they have yet to be incorporated into clinical practice. Comprehensive molecular and genomic analyses using various molecular and next-generation sequencing technology have revealed different degrees of tumor heterogeneity in HCC. It is also to note that inter-tumoral heterogeneity poses severe challenges but also opportunities 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, studying ctDNA could potentially identify more tumor clones and potentially build up a complete picture of tumor heterogeneity in a longitudinal and dynamic manner. The use of circulating tumor DNA (ctDNA) to evaluate and perhaps overcome overall tumor heterogeneity may be an option to help resolve this problem.