1931
Satellite Lesions in Patients with Small
Hepatocellular Carcinoma with Reference to
Clinicopathologic Features
Takuji Okusaka, M.D.1
Shuichi Okada, M.D.1
Hideki Ueno, M.D.1
Masafumi Ikeda, M.D.1
Kazuaki Shimada, M.D.2
Junji Yamamoto, M.D.2
Tomoo Kosuge, M.D.2
Susumu Yamasaki, M.D.2
Noriyoshi Fukushima, M.D.3
Michiie Sakamoto, M.D.4
1
Division of Hepatobiliary and Pancreatic Oncology,
National Cancer Center Hospital, Tokyo, Japan.
2
Division of Hepatobiliary and Pancreatic Surgery,
National Cancer Center Hospital, Tokyo, Japan.
3 showed satellite lesions more frequently than the early HCC and the single nodular
Clinical Laboratory Division, National Cancer
Center Hospital, Tokyo, Japan.
4
Division of Pathology, National Cancer Center
Research Institute, Tokyo, Japan.
Supported in part by a Grant-in-Aid for Cancer
Research from the Ministry of Health, Labour and
Welfare of Japan.
The authors acknowledge the helpful suggestions
of Professor Keigo Yasuda. They thank Ms. Yuriko
Kawaguchi for help with the preparation of the
manuscript.
Address for reprints: Takuji Okusaka, M.D., Hepa-
tobiliary and Pancreatic Oncology Division, Na-
tional Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-
ku, Tokyo, 104-0045, Japan; Fax: 011-81-3-
3545-3567; E-mail: tokusaka@ncc.go.jp
Received October 16, 2001; revision received May
23, 2002; accepted June 3, 2002.
© 2002 American Cancer Society
BACKGROUND. It is not rare to find satellite lesions in patients with small hepato-
cellular carcinoma (HCC). The purpose of this study was to elucidate the factors
associated with satellite lesions in these patients.
METHODS. We investigated the prevalence of satellite lesions, the relationship of
clinicopathologic factors to satellite lesions, and the distance from the main tumor
to the satellite lesion in 149 patients. Patients, who had a solitary HCC of 3.0 cm or
less in diameter but no satellite lesions on preoperative imaging procedures,
underwent potentially curative resection. The main tumors were macroscopically
classified into four groups: early HCC, a vaguely nodular type showing preservation
of the preexisting liver structure; single nodular type; single nodular type with
extranodular growth; and confluent multinodular type.
RESULTS. Of 149 resected specimens, 28 (19%) showed satellite lesions. Of the
clinicopathologic factors investigated, the macroscopic type and tumor differenti-
ation were significantly associated with the prevalence of satellite lesions. Both the
single nodular type with extranodular growth and the confluent multinodular type
type. A significantly higher prevalence of satellite lesions was observed in poorly
differentiated HCC than in well and moderately differentiated HCC. The satellite
lesions were located 0.5 cm or less from the main tumor in 8 (33%) specimens,
0.6 –1.0 cm in 12 (50%), and 1.1–2.0 cm in 4 (17%). No identifiable factors were
significantly related to the distance from the main tumor to the satellite lesion.
However, all satellite lesions located more than 1.0 cm from the main tumor
coexisted with poorly differentiated HCC, which were the single nodular type with
extranodular growth or the confluent multinodular type.
CONCLUSION. In the single nodular type with extranodular growth, confluent multi-
nodular type, and poorly differentiated HCC, extensive treatment achieving a large
safety margin and/or frequent posttreatment follow-up examinations may be
needed because of the high prevalence of satellite lesions. Cancer 2002;95:1931–7.
© 2002 American Cancer Society.
DOI 10.1002/cncr.10892
KEYWORDS: hepatocellular carcinoma, local ablation therapy, satellite lesions,
clinicopathologic factors.
H epatocellular carcinoma (HCC) is one of the most common ma-
lignant tumors in Japan. The screening of high-risk populations
for HCC using ultrasonography and serum ␣-fetoprotein (AFP) levels
has recently increased the number of candidates for effective local
treatments such as hepatic resection.1 However, the majority of pa-
tients with small HCC cannot undergo surgical treatment because of
associated cirrhosis. For these patients, several local ablation meth-
1932 CANCER November 1, 2002 / Volume 95 / Number 9

ods, such as percutaneous ethanol injection (PEI), mi- TABLE 1

crowave coagulation therapy (MCT), and radiofre- Prevalence of Satellite Lesion with Respect
to Clinicopathologic Factors
quency ablation therapy (RFA), have been developed
as minimally invasive therapies and are accepted as No. of patients
alternatives to surgery in patients with small HCC.2– 4 Total no. with satellite
However, the prognosis of patients with small Characteristics of patients lesions (%) P value
HCC is still unsatisfactory because of frequent recur-
Total 149 28 (19)
rence even after complete resection or complete de-
Age (yrs)
struction of the tumor. The high recurrence rate may 21–60 62 12 (19)
be due, at least in part, to untreated satellite lesions, 61–85 87 16 (18) 0.88
which are too small to be detected in imaging meth- Gender
ods before treatment. It is important to analyze the Men 121 20 (17)
Women 28 8 (29) 0.14
factors related to satellite lesions to identify patients at
HBs Ag
high risk and to detect recurrent HCC nodules early Positive 20 4 (20)
enough to reapply effective treatment. The current Negative 129 24 (19) 0.99
study was conducted using 149 resected specimens HCV Ab
with solitary small HCC nodules to analyze satellite Positive 114 19 (17)
Negative 35 9 (26) 0.23
lesions overlooked in pretreatment evaluation with
Alcohol abusea
reference to clinicopathologic features in patients with Positive 68 10 (15)
small HCC. Negative 81 18 (22) 0.24
Total bilirubin (mg/dL)
MATERIALS AND METHODS 0.3–0.9 84 16 (19)
1.0–1.7 65 12 (18) 0.93
The subjects were 170 patients with a solitary HCC of
Albumin (g/dL)
less than or equal to 3.0 cm in diameter who under- 2.6–3.8 77 14 (18)
went potentially curative resection from January 1992 3.9–4.4 72 14 (19) 0.84
to October 1999 at the National Cancer Center Hospi- ICG-15b
tal. Of these 170 patients, 21 patients were excluded 1–20 65 11 (17)
21–57 65 15 (23) 0.38
from this study because satellite lesions and/or portal
Cirrhosis
vein invasion were noted during preoperative evalua- Positive 47 10 (21)
tion, including ultrasonography (US), computed to- Negative 102 18 (18) 0.60
mography (CT) scan, and angiography. In the remain- Tumor size (cm)
ing 149 patients, we assessed satellite lesions in 0.8–2.1 75 13 (17)
2.2–3.0 74 15 (20) 0.65
resected specimens (Table 1). Of the 149 patients, 85
Tumor encapsulation
(57%) patients underwent preoperative transcatheter Positive 129 27 (21)
arterial embolization (TAE). The main surgical proce- Negative 20 1 (5) 0.12
dures applied were partial resection in 92 (62%), sub- Macroscopic type of
segmentectomy in 29 (19%), segmentectomy in 27 tumor
Early HCC 18 0 (0)
(18%), and lobectomy in 1 (1%).
Single nodular type 59 3 (5)
The resected specimens were serially sectioned at Single nodular type
10-mm intervals and examined macroscopically. The with extranodular
criteria used to identify satellite lesions were essen- growth 38 13 (34)
tially those indicated by the Liver Cancer Study Group Confluent
multinodular type 34 12 (35) ⬍ 0.01
of Japan,5 i.e., tumors surrounding the main tumor
Status of differentiationc
with multiple other satellite nodules or small solitary Well 39 3 (8)
tumors located near the main tumor that are histolog- Moderate 71 13 (18)
ically similar or less differentiated than the main tu- Poor 26 12 (46) ⬍ 0.01
mor. The satellite lesions in this study did not include ␣-fetoprotein (ng/mL)
1–20 74 11 (15)
multicentric nodules. Portal vein invasion in the pa-
21–19,930 73 17 (23) 0.28
renchyma was included as satellite lesions in this
study because it is not always easy to make a distinc- HBsAg: hepatitis B surface antigen; HCV Ab: hepatitis C virus antibody; HCC: hepatocellular carcinoma.
tion between them and because portal vein invasion a
Ethanol intake ⱖ 80 g per day for ⱖ 5 years.
b
can also be the origin of satellite lesions. The main Indocyanine green retention at 15 minutes.
c
Evaluation of the histologic grade was not performed for 13 tumors because of extensive necrosis after
tumors were macroscopically classified into four
preoperative transcatheter arterial embolization.
groups according to the following criteria (Fig. 1): early

FIGURE 1. Macroscopic type of main tumor. (A) Early hepatocellular carcinoma (HCC): HCC of a vaguely nodular type showing preservation of preexisting liver
structure. (B) Single nodular type. (C) Single nodular type with extranodular growth. (D) Confluent multinodular type.
HCC, HCC of a vaguely nodular type showing preser-
vation of the preexisting liver structure; single nodular
type; single nodular type with extranodular growth;
and confluent multinodular type.5,6 For light micro-
scopic examination, paraffin-embedded sections were
stained with hematoxylin and eosin. The histologic
grade of tumor differentiation was assigned according
to the classification of the Liver Cancer Study Group of
Japan.5 When two of more histologic patterns were
shown in the same tumor, the predominant pattern
was described. In 13 tumors with extensive necrosis
after preoperative TAE, evaluation of the histologic
grade was not performed.
The relationship beyween clinicopathologic fac-
tors and satellite lesions was also investigated. The
factors were classified as host or tumor related. The
host-related factors were age, gender, hepatitis B sur-
Satellite Lesions in Small HCC/Okusaka et al. 1933
face antigen, hepatitis C virus antibody, alcohol abuse
(ethanol intake ⭌ 80 g per day for ⭌ 5 years), serum
total bilirubin level, serum albumin level, indocyanine
green retention at 15 minutes, and associated cirrho-
sis. The tumor-related factors were tumor size, tumor
encapsulation, macroscopic type, status of differenti-
ation, and serum AFP level. In patients who under-
went preoperative TAE, their values before TAE were
adopted for the assessments of tumor size and serum
AFP level. Each quantitative factor was divided into
two groups by the median. We also assessed the dis-
tance between the main tumor and the satellite lesion.
The distance was defined as the distance from the
margin of the main tumor to the side of the satellite
lesion facing away from the main tumor. When two or
more satellite lesions were detected in the same spec-
imen, the satellite lesion most distant from the main
1934 CANCER November 1, 2002 / Volume 95 / Number 9
tumor was selected. In addition, we evaluated the
differences in the distance from the main tumor to the
satellite lesion with respect to the clinicopathologic
factors.
Frequencies in 2 ⫻ 2 and larger contingency ta-
bles were compared with the chi-square or Fisher
exact test. Distributions of continuous variables were
compared with the Mann–Whitney or the Kruskal–
Wallis test. All P values in this study were two tailed.
Significance was defined as a P value of 0.05 or less.
Statistical analyses were performed with Stat View ver-
sion 5.0 (SAS Institute, Cary, NC).
RESULTS
Of the 149 resected specimens, 28 (19%) showed sat-
ellite lesions. Of the 28 specimens, the maximum di-
ameter of the satellite lesion was 0.1 cm in 6 (20%), 0.2
cm in 8 (30%), 0.3 cm in 5 (18%), 0.4 cm in 4 (14%), and
0.5 cm in 5 (18%). The mean was 0.28 cm, the standard
deviation was 0.14 cm, and the median was 0.25 cm.
The number of satellite lesions per specimen was 1 in
6 (20%), 2 in 7 (25%), 3 in 9 (33%), 5 in 2 (7%), 7 in 1
(4%), and more than 10 in 3 (11%). Table 1 shows the
relationship of the clinicopathologic factors to the sat-
ellite lesions. Of the factors investigated, the macro-
scopic type of tumor and the histologic grade of tumor
differentiation were significantly associated with the
prevalence of satellite lesions. Both the single nodular
type with extranodular growth (34%) and the conflu-
ent multinodular type (35%) showed satellite lesions
more frequently than early HCC (0%; P ⬍ 0.01 for the
single nodular type with extranodular growth, P ⬍ 0.01
for the confluent multinodular type) and the single
nodular type (5%; P ⬍ 0.01 for the single nodular type
with extranodular growth, P ⬍ 0.01 for the confluent
multinodular type). A significantly higher prevalence
of satellite lesions was observed in poorly differenti-
ated HCC (46%) than in well (8%; P ⬍ 0.01) and mod-
erately differentiated HCC (18%; P ⬍ 0.01). The prev-
alence did not differ between the larger (22–30 mm:
20%) and the smaller tumors (21 mm or less: 17%; P
⫽ 0.65). Even in patients with smaller HCC, a signifi-
cantly higher prevalence of satellite lesions was ob-
served in poorly differentiated HCC (5 of 11, 45%) than
in well (2 of 21, 10%; P ⬍ 0.05) and moderately differ-
entiated HCC (6 of 36, 17%; P ⬍ 0.05). The single
nodular type with extranodular growth (8 of 23, 35%)
showed a significantly higher prevalence of satellite
lesions and the confluent multinodular type (4 of 15,
27%) had satellite lesions more frequently, in compar-
ison to early HCC (0 of 12, 0%; P ⬍ 0.05 for the single
nodular type with extranodular growth, P ⫽ 0.10 for
the confluent multinodular type) and the single nod-
ular type (1 of 25, 4%; P ⬍ 0.01 for the single nodular
type with extranodular growth, P ⫽ 0.06 for the con-
fluent multinodular type).
In 4 of the 28 specimens, the distance from the
main tumor to the satellite lesion could not be mea-
sured because the satellite lesion was sectioned sepa-
rately from the main tumor. In the other 24 speci-
mens, the satellite lesions were located 0.5 cm or less
from the main tumor in 8 (33%), 0.6 –1.0 cm in 12
(50%), 1.1–1.5 cm in 1 (4%), and 1.6 –2.0 cm in 3 (13%).
Although no identifiable clinicopathologic factors
were significantly related to the distance from the
main tumor to the satellite lesion, all satellite lesions
located more than 1.0 cm from the main tumor coex-
isted with poorly differentiated HCC, which were the
single nodular type with extranodular growth or the
confluent multinodular type. The satellite lesions in
well and moderately differentiated HCC and/or single
nodular type were located 1.0 cm or less from the
main tumor (Table 2).
DISCUSSION
Many treatment modalities such as surgical hepatic
resection, PEI, MCT, and RFA, have been developed as
effective radical treatments for patients with small
HCC.4 PEI has been the most widely performed and is
now accepted as an alternative to surgery in patients
with small HCC.7,8 However, it has several limitations,
including the uncertainty of tumor ablation and its
unsuitability for large tumors. To overcome these lim-
itations, several other options for local ablation ther-
apy, such as MCT and RFA, have been developed9 –11
and introduced clinically as more effective treatment
modalities to achieve tumor necrosis in fewer treat-
ment sessions than PEI.12–14 TAE, another treatment
option in use, has a marked antitumor effect especially
for expanding encapsulated small HCC, but its effect is
poor for patients with hypovascular or infiltrative
HCC.15
However, the long-term prognosis is still disap-
pointing because recurrence occurs frequently even
after complete local control of the tumor is obtained.
Satellite lesions, which derive from the main tumor via
the portal system, are one of the major causes of HCC
recurrence. Despite recent progress in imaging diag-
nosis, no currently available imaging technique is ad-
equately sensitive to detect small satellite lesions be-
fore treatment. CT scan during arterial portography,
which is one of the most sensitive techniques available
for depicting small nodules, still has several limita-
tions including the frequent appearance of nodular
psuedolesions that mimic HCC.16 –18
It is not rare to find satellite lesions in patients
with small HCC. A previous pathologic study showed
that 37.7% of small HCC of less than or equal to 3.0 cm
 Satellite Lesions in Small HCC/Okusaka et al. 1935

TABLE 2 in diameter had satellite lesions and/or portal vein

Distribution of Distance from the Main Tumor to the SL with Respect invasion including nodules large enough to be identi-
to Clinicopathologic Factors
fied before treatment.6 The current study revealed that
Distance from the main tumor to 19% of HCC nodules of 3.0 cm or less in diameter had
SL (cm) satellite lesions that were not detected during pre-
treatment evaluation. In the clinicopathologic factors
Characteristics 0.1–0.5 0.6–1.0 1.1–1.5 1.6–2.0 Total P value investigated, the macroscopic type of the main tumor
was one of the factors significantly associated with the
Age (yrs)
⫺60 3 4 1 1 9 prevalence of satellite lesions. Both the single nodular
61- 5 8 0 2 15 0.62 type with extranodular growth and the confluent
Gender multinodular type showed satellite lesions more fre-
Men 5 8 1 2 16 quently than early HCC and the single nodular type. A
Women 3 4 0 1 8 0.91
review of 240 autopsy series of patients with HCC
HBs Ag
Positive 1 1 0 1 3 revealed that both the single nodular type with extran-
Negative 7 11 1 2 21 0.76 odular growth and the confluent multinodular type
HCV Ab showed aggressive tumor spread, i.e., a high preva-
Positive 6 9 0 2 17 lence of satellite lesions, portal vein invasion, and
Negative 2 3 1 1 7 0.45
lymphogenous and hematogenous metastasis.19 Our
Alcohol abusea
Positive 3 4 0 2 9 study indicated that aggressive tumor spread in the
Negative 5 8 1 1 15 0.62 single nodular type with extranodular growth and in
Total bilirubin (mg/dL) the confluent multinodular type was observed even in
⫺0.9 5 8 1 0 14 patients with small HCC.
1.0- 3 4 0 3 10 0.15
The findings in this study suggested that a de-
Albumin (g/dL)
⫺3.8 4 5 1 1 11 tailed pretreatment imaging diagnosis of the macro-
3.9- 4 7 0 2 13 0.68 scopic type may be helpful in predicting satellite le-
ICG-15b sions in patients with HCC. However, to our
⫺20 4 4 1 0 9 knowledge, the role of imaging modalities in the clas-
21- 4 7 0 3 14 0.27
sification of the macroscopic type in patients with
Cirrhosis
Positive 4 2 0 2 8 small HCC has not yet been fully evaluated. Conven-
Negative 4 10 1 1 16 0.21 tional CT scans and magnetic resonance imaging
Tumor size (cm) (MRI) are insufficiently sensitive, whereas conven-
⫺2.1 5 5 1 2 13 tional B-mode US provided a correct diagnosis for
2.2- 3 7 0 1 11 0.57
macroscopic type in 61% of patients with small
Tumor encapsulation
Positive 7 12 1 3 23 HCCs.20 –22 Recent advances in technology have facil-
Negative 1 0 0 0 1 0.55 itated morphologic characterization of small tumors
Macroscopic type of tumor by imaging modalities, including US with a micro-
Early HCC 0 0 0 0 0 bubble contrast agent, dynamic thin-sliced CT scans,
Single nodular type 1 2 0 0 3
and fast three-dimensional gadolinium-enhanced
Single nodular type with
extranodular growth 4 5 0 2 11 0.88 MRIs. These diagnostic approaches improve imaging
Confluent multinodular quality and contribute positively to the characteriza-
type 3 5 1 1 10 tion of the hepatic nodule.23–27
Status of differentiation The histologic grade of tumor differentiation was
Well 1 2 0 0 3
another factor significantly related to the prevalence
Moderate 5 7 0 0 12
Poor 2 3 1 3 9 0.23 of satellite lesions. Several studies reported that a low
␣-fetoprotein (ng/mL) degree of tumor cell differentiation was a risk factor
⫺20.9 2 5 1 1 9 for HCC recurrence after hepatic resection or PEI.28 –30
21.0- 6 7 0 2 15 0.51 These findings were supported by the findings of this
study, in which a higher prevalence of satellite lesions
SL: satellite lesion; HBsAg: hepatitis B surface antigen; HCV Ab: hepatitis C virus antibody; HCC:
hepatocellular carcinoma. was noted in patients with small HCC with a lower
a
Ethanol intake ⱖ 80 g per day for ⱖ 5 years. grade of tumor differentiation. Tumor biopsy before
b
Indocyanine green retention at 15 minutes. ablation therapy may be beneficial to predict satellite
lesions not detected during the pretreatment evalua-
tion. Tumor biopsy using a 21-gauge needle has been
performed routinely in our hospital before ablation
1936 CANCER November 1, 2002 / Volume 95 / Number 9
therapy for patients with small HCC except for sub-
capsular HCC.31 This procedure is safe with a low risk
of tumor seeding, although direct puncture of subcap-
sular HCC or the use of a large needle may cause
hemorrhage and tumor dissemination.31–38
Tumor size was not associated with the preva-
lence of satellite lesions in patients with small HCC. In
HCC of 2.1 cm or less in diameter, the macroscopic
type and tumor differentiation were significantly as-
sociated with the prevalence of satellite lesions. In the
single nodular type with extranodular growth, the con-
fluent multinodular type, and in poorly differentiated
HCC, extensive treatment and/or frequent posttreat-
ment examinations may be needed even though the
tumor is relatively small.
In this study, the satellite lesions were located 2.0
cm or less from the main tumor, but no identifiable
factors were related to the distance from the main
tumor to the satellite lesion. Local ablation therapy
has cell-killing effects on the main tumor and on the
adjacent surrounding tissue including the satellite le-
sion.39,40 Heat ablation therapy is more effective than
the classic method (e.g., PEI) to achieve a wide safety
margin.41– 44 The multimodality treatment approach
combined with ablation therapy and transcatheter ar-
terial balloon occlusion/embolization has the poten-
tial to enlarge the volume to be treated.45–50 Extensive
therapies or hepatectomy with a wide resection mar-
gin may be applied to the single nodular type with
extranodular growth, the confluent multinodular type,
and poorly differentiated HCC, all of which have a
high prevalence of satellite lesions located far from the
main tumor. However, there is a possibility that some
satellite lesions will survive even after initial treatment
appeared to be successful. To detect the untreated
nodules early enough to reapply effective treatment,
frequent follow-up examinations after treatment may
be needed especially in the single nodular type with
extranodular growth, the confluent multinodular type,
and poorly differentiated HCC.
In conclusion, this study demonstrated that the
macroscopic type of tumor and tumor differentiation
were significantly associated with the prevalence of
satellite lesions. Both the single nodular type with
extranodular growth and the confluent multinodular
type showed satellite lesions more frequently than
early HCC and the single nodular type. In addition, a
significantly higher prevalence was observed in poorly
differentiated HCC than in well and moderately differ-
entiated HCC. The findings in the current study may
be helpful in determining treatment strategies and
follow-up examination schedules after treatment of
patients with small HCC.
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