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Wang et al. Hepatoma Res 2018;4:14 I http://dx.doi.org/10.20517/2394-5079.2018.16 Page 5 of 10

THE CLONAL ORIGIN OF MHCC
MHCC is a common clinical form of HCC. At present, scholars in various countries, including some
international standards, have not yet reached a consensus on the clinical diagnosis and staging of MHCC.
For example, there is controversy about ≥ 2 nodules or ≥ 3 nodules as the standard of MHCC . The
[56]
Barcelona clinic liver cancer (BCLC) staging classification defined ≤ 3 nodules, ≤ 3 cm as stage A, called the
early stage; ≥ 4 tumors of any size, or > 3 cm, 2-3 tumors are classified as stage B, called the intermediate
[57]
stage, and defined as MHCC . Therefore, MHCC is not considered as early form of HCC in BCLC staging
classification. Accordingly, the guidelines of HCC in Europe and America also recommend TACE/sorafenib
as a first-line treatment for MHCC [58,59] . However, if such kind of HCC occurred based on clonal origin of
MO type, then they should not be considered pathobiologically as in the intermediate progression stage,
and their treatment strategy will also be different accordingly. As the exploration of different treatment
with BCLC intermediate stage of HCC, hepatic resection for some patients can obtain better prognosis than
conservative treatment [60,61] .

With the increase of nodule and the scattered nodule, the prognosis of the patients is worse [62-64] . Therefore,
the current clinical study is paying more attention to the screening of radical treatment for MHCC [65,66] .
[67]
Huang et al. studied 102 MHCC patients with less than 3 nodules, and found that the presence of MVI
is an independent risk factor for the patients of early recurrence (< 1 year) (HR, 4.02, 95% CI, 1.42-11.39,
[68]
P = 0.009). Nojiri et al. retrospectively analyzed 107 patients of MHCC who underwent R0 resection and
found that, for the patients with > 4 nodules, vascular invasion was an independent risk factor for long-term
survival (1-year overall survival 71.1% vs. 82.4%, 3-year overall survival 36.9% vs. 61%, 5-year overall survival
0% vs. 25.4%, P = 0.0035). In view of vascular invasion, it is an important indication for the occurrence
of MHCC as IM type. To sum up, no matter the number of nodules, vascular invasion are always the
important prognostic factors for MHCC. Referring to the correlation between vascular invasion and IM
type clonal origin, effective screening of MO type MHCC patients for actively radical treatment has become
an important point of MHCC clonal origin research.

Similar to the research of RHCC clonal origin, the study of MHCC clonal origin also begins with the HBV-
DNA integration site analysis. Govindarajan et al. and Aoki et al. analyzed the HBV-DNA integration
[69]
[70]
sites in 2 cases of MHCC, respectively, and preliminarily established the concept of IM type and MO type
in MHCC. After that, some scholars used different methods, such as analysis of methylation pattern of
X-chromosome-linked human androgen receptor gene, mitochondrial D-loop mutations analysis, DNA
fingerprinting analysis, analysis of difference of tumor suppressor gene promoter region methylation, to
confirm the existence of IM type and MO type MHCC [71-74] . Subsequently, scholars began to pay attention
[75]
to the proportion of IM type and MO type in MHCC. Hsu et al. analyzed the HBV-DNA integration
site of 25 cases of MHCC, including the main tumor, satellites and metastatic loci, and found that the IM
[76]
type and MO type accounted for 60.7% and 39.3%, respectively. Tsuda et al. detected the alleles LOH of
chromosome 16 in 19 MHCC patients, and found that the IM type and MO type accounted for 52.4% and
47.6%, respectively. Hui et al. performed DNA ploidy analysis of 62 tumor nodules in 26 MHCC patients,
[77]
and found that IM type and MO type accounted for 53.8% and 46.2%, respectively. Based on our detection
of the clonal origin of 439 cases of MHCC in Eastern Hepatobiliary Surgery Hospital, IM type and MO
type MHCC account for 51.9% and 48.1%, respectively (unpublished data). Referring to the clonal origin
of RHCC, we believe that MHCC is likely to have the same clonal origin patterns with RHCC [Figure 3].
Therefore, the choices of clinical treatment patterns for patients with MHCC should be based on the clonal
origin patterns of MHCC in order to get better prognosis for these patients.

With the development of the next-generation sequencing technology, the understanding of clonal origin
of MHCC can be penetrated into the level of specific gene and whole gene expression profiles. Xue et al.
[31]
performed exome and low-depth, whole-genome sequencing for 43 nodules of primary tumors, satellite foci,