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Page 2 of 10 Wang et al. Hepatoma Res 2018;4:14 I http://dx.doi.org/10.20517/2394-5079.2018.16

Figure 1. Hepatocellular carcinoma with different histological appearance and similar histological appearance. A-1: pseudoglandular
pattern; A-2: thick trabecular pattern; B-1: thick trabecular pattern; B-2: thick trabecular pattern

and the mortality rate ranked the third . With the development of time, the hepatic surgery has made great
[1]
progress, and liver resection has become a routine method for the treatment of HCC . However, the hepatic
[2]
surgery is still facing two major obstacles. One is the treatment of recurrent hepatocellular carcinoma
(RHCC). It was reported that the 5-year recurrence rate after hepatic resection of HCC is about 70% to
80%, or even higher . Meanwhile, there is no consensus on the clinical treatment options for RHCC.
[3-7]
Secondly, it is the treatment of multinodular hepatocellular carcinoma (MHCC). It has approved that the
patient’s prognosis is poorer accompanied by the increased tumor nodules, especially > 3 foci . One of the
[8]
material causes for two major obstacles stems from the unprecise judgment of the clonal origin of RHCC
and MHCC. It has affirmed the secondary tumor (synchronous or metachronous) was the core to directly
reflect the biological behavior and determine patient’s prognosis [9-12] . For our practice, we found that two
tumor nodules in one patient may have similar or different histological appearance, which may suggest the
clonal origin of the tumors [Figure 1]. However, this judging method largely depends on the experience of
the pathologist, which is not objective and accurate. Obviously, the clonal origin detection is unquestionably
the check point to explore the biological behavior of HCC.

HCC is a malignant tumor with high potential of recurrence and metastasis . However, the clonal origin
[13]
of RHCC/MHCC cannot be determined by simple clinical indicators and histopathology . Consequently,
[14]
the molecular pathological clonal origin detection is a new method to objectively determine the early,
intermediate, and advanced stage of HCC in biological behavior and construct the basement of HCC
molecular classification . In other word, the clonal origin model directly affects the choice of clinical
[15]
treatment.

Therefore, this review article briefly summarizes some relevant progresses of molecular pathological clonal
origin of RHCC and MHCC. We searched all available publications regarding “clonal origin”, “recurrent
hepatocellular carcinoma”, “multinodular hepatocellular carcinoma”, “intrahepatic metastasis”, and
“multicentric occurrence” in the PubMed and focused the data mainly based on the high quality full-text
format.

THE CLONAL ORIGIN OF HCC
The exploration of the clonal origin of the malignancy started in the blood system tumor [16,17] . Currently, it
has approved that multiform clonal origins exist in malignant tumor. Identifying the clonal origin is of great
significance for exploring tumor occurrence and evaluating tumor evolution [18-22] . For solidary tumor, there
are two types of clonal origin, monoclonal origin and polyclonal origin . Whether the secondary tumor
[23]
is synchronous or metachronous, it may originate from intratumor metastasis of primary tumor (IM type);
peradventure, it may be unrelated to the primary tumor, but from the normal cells which have adequate
malignant mutation accumulation (MO type) . Similarly, IM type HCC originates from the primary HCC
[24]
with low degree of differentiation, incomplete envelope, widespread microvascular invasion (MVI) or even
portal vein invasion. Among all of risk factors, MVI is considered to be the core factor in the occurrence
of IM type HCC. According to our research on 686 HCC patients, the incidence of MVI was about 42% .
[25]