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Page 2 of 16 Zhang et al. Hepatoma Res 2020;6:30 I http://dx.doi.org/10.20517/2394-5079.2020.17

INTRODUCTION
Liver cancer is the sixth most prevalent cancer and the fourth leading cause of cancer-related death
worldwide. Hepatocellular carcinoma (HCC), mostly due to liver cirrhosis, accounts for 75%-80% of all liver
[1]
cancers . Heterogeneity is the main biological characteristic of HCC, which manifests through different
biological behaviors of each phenotype and ultimately, affects patient prognosis and treatment efficacy.
Various aggressive biological behaviors including poor differentiation, microvascular invasion (MVI),
intracellular fat accumulation, invasive growth, bile duct invasion or tumor thrombosis, and tumor spread
and metastasis, have been reported to have an impact on clinical outcomes and the prognosis of HCC
[2-6]
patients .

Liver imaging, a noninvasive method for visualizing tumor morphology and function, can provide a clear
diagnosis and assessment of HCC in the presence of risk factors, and has flourished in recent decades with
the potential to better depict the complex biological behaviors of HCC with relevant morphological and
quantitative biomarkers [7-13] . Traditional imaging, including contrast-enhanced ultrasound, multi-phase
dynamic enhanced computed tomography (CT) or magnetic resonance imaging (MRI), and fluoro-deoxy-
glucose/positron emission tomography (FDG/PET), play significant roles in the characterization of HCC as
most have a typical blood supply and morphological characteristics. Functional imaging, including diffusion-
weighted imaging (DWI), chemical-shift MRI, magnetic resonance elastography (MRE), and MRI with liver-
[14]
specific contrast, can provide cellular and metabolic information for the grading and staging of HCC .
Furthermore, improvements in advanced imaging analysis, including radiomics and artificial intelligence
(AI), have introduced enormous potential for assessing the aggressiveness of HCC and prognostication of
patients. Table 1 shows the aggressive biological behaviors associated with poor prognosis of HCC patients
and their pathological basis, as well as morphological and qualitative imaging biomarkers that can be used to
evaluate and predict biological behaviors. In addition, HCC is the result of multifactor synergistic damage,
and various factors related to genetics, molecular pathology and immunohistochemistry also have an impact
[15]
on HCC differentiation and prognosis .

This article reviews the imaging biomarkers for aggressive behaviors associated with a poor prognosis
in HCC patients, and the roles of different imaging methods and related biomarkers in the evaluation
and prediction of these behaviors [Table 2]. A better understanding of these imaging features and their
correlation with pathology can help clinicians to design the most appropriate treatment plans for HCC. In
addition, a combination or confrontation of imaging signs with other biomarkers may be a direction for
future research to better predict the prognosis of HCC.

POOR DIFFERENTIATION
Differentiation refers to the dedifferentiation of premalignant nodules until the development of HCC
[16]
itself. The degree of differentiation of HCC is the key to prognosis of HCC patients . Several pathological
alterations are involved in loss of differentiation in HCC such as neoangiogenesis, disordered cellular
structure, impairment of Kupffer cells and hepatocytes, and increased glucose metabolism in tumor cells.

NEOANGIOGENESIS
Neovascularization provides the basis for oxygen and nutrition for tumor growth, progression and
metastasis. The unpaired arteries are new vessels which form through neovascularization, and play a crucial
[17]
role both in the occurrence and development of HCC .
As most HCCs show a typical enhancement pattern such as hyperenhancement in the hepatic arterial phase,
and washout appearance in the portal venous and/or delayed phases relative to the surrounding tissue,
traditional imaging technologies such as contrast-enhanced ultrasound (CEUS), dynamic contrast-enhanced