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Page 2 of 14 Kobayashi et al. Hepatoma Res 2020;6:36 I http://dx.doi.org/10.20517/2394-5079.2020.24

70%-90% of primary liver cancer is hepatocellular carcinoma (HCC). Hepatitis B or C virus infections and
chronic inflammation due to alcohol intake are the main risk factors of HCC. In Japan, such high-risk
patients have been identified and early detection and treatment systems have been established.

One of the key approaches for the early detection of HCC is to understand its characteristic imaging findings
of nodules undergoing the multi-step hepatocrcinogenesis process. In other words, picking up early HCC
within various types of pre-malignant nodules in cirrhotic livers is essential for the early detection of
clinically significant HCC.

For such early detection, contrast enhanced CT, MRI and contrast enhanced ultrasound (CE-US) might be
used as imaging modalities. In particular, recent advancements in ultrasonographic contrast agents have
enabled monitoring of detailed haemodynamics and Kupffer cell function of liver nodules. Compared to CT
and MRI, CE-US is a powerful tool for the analysis of multistep hepatocarcinigenesis because it enables real
time monitoring of the dynamics of the contrast agent within the liver. However, we do not have enough
experience to discuss the advantages of CE-US in multi-step hepatocarcinogenesis. Therefore, in this article,
we will review the imaging findings of multi-step hepatocarcinogenesis on CT and MRI instead, and to focus
on the early detection of malignant cirrhotic nodules.

MULTI-STEP HEPATOCARCINOGENESIS
Hepatocarcinogenesis exhibits a multi-step process. It starts from a regenerative nodule in cirrhosis or as a
[2]
dysplastic nodule (DN), which is a precancerous condition, and progresses to advanced HCC [Figure1] . A
considerable proportion of HCC arise through multi-step hepatocarcinogenesis while other HCCs develop
[2,3]
de-novo .

Therefore, in high-risk patients, it is important to monitor the process of malignant transformation from
precancerous nodules to overt malignant nodule in HCC. Treatment of malignant nodules in early stages
might thus be expected to lead to an improved prognosis for HCC patients if detected early.

PATHOLOGICAL DIFFERENTIATION OF MALIGNANT FROM BENIGN NODULES
Histopathologically, the multi-step hepatocarcinogenesis process is observed when moderately or poorly
[4]
differentiated HCC (advanced HCC) develops in the nodule of well differentiated HCC [Figure 1] . This
nodule-in-nodule appearance differs however, when considering definitions in pathology (malignant focus
in premalignant nodule) and imaging (hypervascular focus in nonhypervascular nodule). Similar nodule-in-
nodule structures are also observed in diagnostic imaging although the detection rate is not high in routine
CT and MRI. However, when the characteristics of the inner nodule are different from the surrounding
nodule, such as a hypervascular foci within a hypovascular nodule (as discussed later), or the absence of a
superparamagnetic iron oxide (SPIO) uptake foci within the SPIO-uptake nodule, these different findings
within the same nodule would represent imaging findings of multi-step hepatocellular carcinogenesis
[Figure 2].

Pathologically, DNs are classified into low grade DN (LGDN), which is close to normal, and high grade DN
(HGDN), which is close to malignancy. The nodule that is histologically more malignant than HGDN is
called early HCC. The clinical and pathological characteristics of the nodules which develop in multi-step
[5,6]
hepatocarcinogenesis in cirrhosis are shown in Figure 3 .

To differentiate HGDN from early HCC histologically, the findings of tumor cell invasion in the remaining
[5,7]
portal tract (stromal invasion) is an important hallmark of early HCC .