1) The study examined 100 autopsied livers containing metastatic cancers and found that metastases were most commonly of the multinodular type (65%). 2) Metastases from colon and lung cancers most often showed intraparenchymal growth within the liver tissue (92.3% and 87.5%, respectively), while metastases from gallbladder/bile duct cancer less frequently showed intraparenchymal growth (35.7%). 3) Micrometastases under 1mm from lung, colon, and pancreas cancers predominantly displayed a replacement growth pattern, replacing hepatocytes. Micrometastases from stomach and gallbladder/bile duct cancers predominantly showed a sinusoidal growth pattern within liver

1. Histologic Growth Patterns of Metastatic Carcinomas of the Liver
Noboru Terayama, Tadashi Terada and Yasuni Nakanuma
Second Department of Pathology, Kanazawa University School of Medicine, Kanazawa
One hundred autopsied livers containing metastatic cancers were studied patholgically. Macro-
scopically, the cancers were of the multinodular type in 65.0% of cases, massive type in 17.0%
and portal tract type in 8.0%. Among liver metastases from colon and lung cancers, most cases
showed predominantly intraparenchymal growth (92.3% and 87.5%, respectively). In contrast,
among liver metastases from gallbladder/bile duct cancer, intraparenchymal growth was less fre-
quent (35.7%). With regard to the histologic growth pattern at the boundary of the liver
metastases, in micrometastases less than 1 mm in diameter a replacement growth pattern was
predominant among metastases from lung, colon and pancreas cancers (69.7%, 79.3% and
66.7%, respectively), whereas a sinusoidal growth pattern was predominant in those from gas-
tric and gallbladder/bile duct cancers (48.5% and 66.7%). Among macrometastases of the liver
over 20 mm in diameter, an expansive growth pattern was predominant, irrespective of the
cancer primary site. Thus metastatic liver cancers showed changes in growth patterns accord-
ing to the size of the metastatic tumors.
(Jpn J Clin Oncol 26: 24-29, 1996)
Key words: Liver—Metastasis—Pathology
Introduction
Many malignant neoplasms often metastasize to
the liver, and the frequency of liver metastasis is
much higher than that of primary liver cancers.1
'
Eggel classified primary liver cancer as nodular
type, massive type, or diffuse type according to its
gross appearance.2
' The histologic patterns of
tumor growth of hepatocellular carcinoma at
tumor-non-tumor boundaries were described by
Nakashima et al.3)
as follows: sinusoidal pattern,
cancer cells growing in sinusoids at the boundary
and compressing the liver cell cords; replacement
pattern, cancer cells replacing hepatocytes along the
liver cell cords, and the cancer cells adhering to
each other; encapsulated pattern, cancer cells grow-
ing in an expansive manner and acquiring a fibrous
capsule. Certain metastatic cancers in the liver show
sinusoidal growth and a few have surrounding fi-
brous capsules." However, little attention has been
directed toward the replacement growth pattern of
metastatic liver cancer. Furthermore, the difference
Received: May 2, 1995
Accepted: August 16, 1995
For reprints and all correspondence: Yasuni Nakanuma,
Second Department of Pathology, Kanazawa University
School of Medicine, Kanazawa 920
in predominant growth pattern according to the size
of metastatic cancers in the liver has not been ad-
dressed.
Recent progress in diagnostic modalities has made
it possible to analyze the precise morphologic fea-
tures of metastatic liver cancers.4
"6
' In this- study
we investigated the pathology of metastatic liver
cancer to elucidate the histologic differences in in-
dividual primary sites and to correlate the growth
pattern of metastatic liver cancer with the primary
site and the size of the metastatic tumor in order
to improve the interpretation of diagnostic imaging
and the planning of treatment for metastatic liver
cancer.
Materials and Methods
Histologic Specimens
One hundred autopsied livers with metastatic
cancers were studied. The background factors are
summarized in Table I. The patients comprised 71
men and 29 women, with a mean age of 65.7 <
12.3 years. The mean weight of the liver was
1729± 942 g. Cancer primary sites were as follows:
lung 24; pancreas 21; stomach 18; gallbladder/bile
duct 14; colon 13; kidney 3; other cancers 7. There
was no difference in liver weight or patient age
24 Jpn J Clin Oncol 26(1) 1996
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2. HISTOLOGIC GROWTH PATTERNS OF LIVER METASTASES
Table I. Main Clinicopathological Features of Autopsy Cases with Liver Metastases
Primary site
Lung
Pancreas
Stomach
GB/Bile duct
Colon
Others
GB, gallbladder: *,
Number of cases
24
21
18
14
13
10
years (mean±SD); f
,
Sex
Male
22
19
15
5
6
4
gram (mean±SD).
Female
2
2
3
9
7
6
Age of patients *
66.3 ±10.1
67.4±10.4
63.3 ±14.9
69.5 ±10.1
63.9±15.0
62.4±12.1
Weight of liver f
1501 ±612
1455 ±377
2099 ±1078
1380 ±245
2317±1539
1996±1015
among the primary sites. Each liver was cut into
1-cm slices and fixed in 10% buffered formalin.
From each liver, we obtained several specimens
containing various sizes of metastatic tumors, and
embedded then in paraffin. Several 5-/mi-thick sec-
tions were obtained from each paraffin-embedded
block and stained with hematoxylin-eosin, Gomori's
reticulin and elastica van Gieson.
Macroscopic Findings
Livers with metastatic tumors were classified by
gross macroscopic appearance in accordance with
Eggel's classification2
' into nodular, massive and
diffuse types. Nodular type was subdivided into
solitary, multinodular and fused types. Livers show-
ing enlarged portal tracts and linear or small nodu-
lar tumors in the vicinity of the portal tracts
considered to be lymphangiosis carcinomatosa7
'8)
were classified as having portal tract-type
metastases.
Microscopic Evaluation
Predominant Sites of Growth: The growth sites of
metastatic liver cancer were classified into two types
according to light microscopic findings: portal tract
growth, metastatic tumors growing within and/or
along the portal tracts; parenchymal growth,
metastatic tumors growing in and/or toward the
hepatic parenchyma with no or little portal tract
growth; intermediate type, including both of the
precious types of growth.
Histologic Growth Patterns: Histologic growth pattern
at the boundary between the tumor and hepatic
parenchyma was classified into five types: sinusoi-
dal, replacement and encapsulated growth patterns,
which were described in hepatocellular carcinoma
by Nakashima et a/.,3)
expansive growth pattern
and unclassified pattern. The histologic features of
the individual growth patterns are as follows.
Sinusoidal growth pattern; tumor cells infiltrate into
the sinusoids at the boundary of the metastasis,
and liver cells are left inside the boundary of the
tumor. Replacement growth pattern; tumor cells
grow within the liver-cell plates, and replacing
tumor cells are in continuity with liver cells. In this
pattern, compression and destruction of the liver
cells close to the tumor cells are a little more
prominent than in the replacement growth pattern
in hepatocellular carcinoma. Expansive gorwth pat-
tern; tumor cells compress the liver-cell plates and
sinusoids and make the liver cells atrophic. In this
pattern, the border of the tumor is somewhat even
and smooth. Encapsulated growth pattern; metastat-
ic tumor foci have an enclosing fibrous capsule.
The correlation of the ratios of the individual
growth patterns and the sizes of the metastatic
tumors were evaluated at each primary site.
Results
Macroscopic Findings
Table II shows the ratios of the macroscopic
types of metastatic liver cancers. Massive type and
nodular type comprised 17 (17%) and 73 (73%)
cases, respectively. There were no cases showing the
diffuse type in the present study. Among nodular-
type metastases, there were 3 of the solitary type
(3%), 65 of the multinodular type (65%) and 5 of
the fused multinodular type (5%). The portal tract
type was seen in 8 cases (8%). In a case of pan-
creatic cancer and a case of uterine cancer,
metastases in the liver were invisible, macroscopical-
ly. Among all primary sites, the multinodular type
was most frequent. Primary sites of metastatic liver
cancers showing the portal tract type included 2
cases of pancreatic cancer, 2 cases of gastric cancer
and 4 cases of gallbladder/bile duct cancer. Four of
8 cases were poorly differentiated adenocarcinoma.
Microscopic Evaluation
Predominant Sites of Growth: Cases showing
predominant parenchymal growth were seen in
92.3% of colon cancers, 87.5% of lung cancers,
66.7% of pancreas cancers, 61.1% of stomach
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3. TERAYAMA ET AL.
Table II. Macroscopic Classification of Liver Metastases
Number (%) of cases
Primary site
Lung
Pancreas
Stomach
GB/Bile duct
Colon
Others
Number of
cases
24
21
17
14
13
10
Massive
type
0
3(14.3)
5(27.8)
4(28.6)
2(15.4)
3(30.0)
Solitary
0
0
1(5.6)
0
2(15.4)
0
Nodular type
Multiple
22(91.7)
15(71.4)
9(50.0)
6(42.8)
7(53.8)
6(60.0)
Fused multiple
2(8.3)
0
1(5.6)
0
2(15.4)
0
r
Total
24(100)
15(71.4)
11(61.2)
6(42.8)
11(84.6)
6(60.0)
Portal tract
type
0
2(9.5)
2(11.1)
4(28.6)
0
0
Invisible
type
0
1(4.8)
0
0
0
1(10.0)
GB, gallbladder. Diffuse type not found.
cancers, and 35.7% of gallbladder/bile duct
cancers. Among liver metastases from colon cancer
and lung cancer, the proportion of the cases show-
ing parenchymal growth was higher than that for
gallbladder/bile duct cancer (iJ
<0.05). On the other
hand, cases showing predominant portal tract
growth were seen in 35.7% of gallbladder/bile duct
cancers (Fig. 1), 19.0% of pancreas cancers, 16.7%
of stomach cancers, and 4.2% of lung cancers. In
the ramaining cases: 28.6% of gallbladder/bile duct
cancers, 22:2% of stomach cancers, 14.3% of pan-
creas cancers, 8.3% of lung cancers and 7.7% of
colon cancers, both parenchymal growth and por-
tal tract growth were seen equally.
Histoiogic Growth Patterns: In small metastases in
the liver less than 1 mm in diameter, a replacement
growth pattern (Fig. 2) was predominant for lung
cancer (69.7%), pancreas cancer (79.3%) and colon
cancer (66.7%). In these cases, the proportion
showing an expansive growth pattern increased as
the metastatic tumors grew. In metastases over
20 mm in diameter, an expansive growth pattern
(Fig. 3) was seen in 62.5%, 50.0% and 76.9%,
respectively. On the other hand, a sinusoidal
growth pattern (Fig. 4) was predominant in liver
metastases less than 1 mm in diameter from gastric
cancer and gallbladder/bile duct cancer (48.5% and
66.7%), followed by a replacement growth pattern
(39.4% and 26.7%, respectively). The proportion
showing an expansive growth pattern also increased
as the metastatic tumors grew. In these cases, an
expansive growth pattern was also predominant in
lesions over 20 mm in diameter (84.6% and
47.4%). Table III shows the proportions of the in-
dividual growth patterns.
A fibrous capsule around the metastatic liver
cancer was seen in two cases of colon cancer (Fig.
5) and two cases of renal cell cancer. Fibrous septa
in the metastasis were seen in two cases of colon
cancer and one case of small cell lung cancer. One
case of follicular carcinoma of the thyroid and
Fig. 1. Growth and spread of metastatic carcinoma of
the liver into the portal tract. Carcinoma cells are seen in por-
tal veins, lymphatic and connective tissue in the portal tract.
Metastasis from gallbladder cancer.
papillary carcinoma of the stomach showed a par-
tial fibrous capsule and fibrous septa. A case of
transitional cell carcinoma of the renal pelvis
showed microscopic intraductal growth.
Discussion
In this study, we classified macroscopically cases
of metastatic carcinoma of the liver resembling lym-
phangiosis carcinomatosa of the lung7>8)
as the
portal tract type. In such cases, tumor cells enter
the lymphatics in the portal tracts, spread to the in-
terstitium along the lymphatics, spread from the
hepatic hilum to the peripheral liver along the por-
tal tracts, and linear or small nodular tumors are
observed in the vicinity of the portal tracts.7
'8)
Poorly differentiated adenocarcinoma was most fre-
quent in the portal tract type. Particularly in gas-
tric cancer, pancreas cancer, and gallbladder/bile
duct cancer, the portal tract type was more fre-
quent than in other primary sites. With regard to
Jpn J Clin Oncol 26(1) 1996
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4. HISTOLOGIC GROWTH PATTERNS OF LIVER METASTASES
(a)
Fig. 2. Replacement growth pattern, metastasis from adenocarcinoma of the lung, (a) HE and (b) reticulin stain. Metastatic
carcinoma cells within liver-cell plates covered with reticulin fibers. M, metastasis.
Fig. 3. Expansive growth pattern, metastasis from colon cancer, (a) HE and (b) reticulin stain. Metastatic carcinoma
shows expansive growth. Liver-cell plates are compressed and atrophic. M, metastasis.
Fig. 4. Sinusoidal growth pattern, metastasis from colon cancer, (a) HE and (b) reticulin stain. Metastatic carcinoma
cells show intrasinusoidal growth and are present between liver-cell plates. M, metastasis.
27
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5. TERAYAMA ET AL.
Table
Primarv site
Lung
Pancreas
Stomach
GB/bile duct
Colon
III. Proportion of
Size of
metastasis (mm)
20 <
<20
< 3
< 1
20 s
<20
< 3
<I
20 <
<20
< 3
< 1
20 <
<20
< 3
< 1
20 <
<20
< 3
< 1
Five Types of
Replacing
31.3
18.9
40.4
69.7
25.0
37.5
60.0
79.3
0
22.2
23.5
39.4
15.8
31.6
28.0
26.7
7.7
7.7
12.5
66.7
Growth Patterns in
Proportion
Expansive
62.5
75.7
51.1
10.6
50.0
40.6
34.3
0
84.6
59.3
52.9
6.1
47.4
36.8
28.0
6.7
76.9
84.6
75.0
6.7
Relation to
of growth
Sinusoidal
0
0
2.1
13.6
4.2
3.1
0
17.2
7.7
7.4
20.6
48.5
0
0
0
66.7
0
0
12.5
26.7
i Size of Metastatic
pattern (<%)
Encapsulated
6.3
0
0
0
0
0
0
0
0
0
0
0
10.5
0
0
0
15.4
0
0
0
Tumor
Unclassified
0
5.4
6.4
6.1
20.8
18.8
5.7
3.4
7.7
11.1
2.9
6.1
26.3
31.6
44.0
0
0
7.7
0
0
Fig. 5. Encapsulated growth pattern. A metastatic car-
cinoma from cancer is surrounded by a fibrous capssule.
the predominant sites of growth of metastatic liver
cancers, prominent portal tract growth abounded in
poorly differentiated adenocarcinoma, particularly
metastases from the stomach, pancreas and gall-
blaldder/bile duct. These macro- and microscopic
findings may be related to the anatomical relation-
ship between the primary sites and the liver, and
the tendency for the tumor cells to enter the lym-
phatic channels. It is considered that these findings
may be useful for helping to indicate the primary
site.
The present study demonstrated that a replace-
ment growth pattern was not rare in metastatic
liver cancers. Especially in those from the lung,
pancreas and colon, the smaller the size of the
metastatic tumor, the higher the frequency of a
replacement growth pattern. Compared with the
replacement growth of hepatocellular carcinoma
noted by Nakashima et a/.,3)
even the tumors grew
within the liver-cell plates, although destruction and
compression of hepatocytes were more prominent
than in hepatocellular carcinoma. In the cases of
gastric cancer and gallbladder/bile duct cancer, a
sinusoidal growth pattern was predominant in small
metastases. Similar to the other primary sites, the
proportion of the expansive growth pattern in-
creased as the size of the metastases increased. It is
suggested that metastatic liver cancers grow in the
liver-cell plates and/or sinusoids at first, then the
speed of growth exceeds the rate of hepatocyte
replacement by tumor cells or invasion of tumor
cells into the sinusoids. Otherwise, the size of the
metastatic tumor and growth pattern might be as-
sociated with the intensity of adhesion among
tumor cells. That is, tumor cells with strong adhe-
sion form large metastatic nodules and show expan-
sive growth, and those with weak adhesion form
small nodules and show a replacement growth
pattern.
Small metastatic liver cancers are supplied by sur-
rounding hepatic sinusoids, and as the metastatic
28 Jpn J Clin Oncol 26(1) 1996
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6. HISTOLOGIC GROWTH PATTERNS OF LIVER METASTASES
tumor grows, newly formed blood vessels supply
them.9)
That is, metastatic liver cancers showing a
replacement or sinusoidal growth pattern are possi-
bly supplied by sinusoidal blood flow. The switch-
ing of the blood supply to metastatic liver cancers
is thought to be closely related to the change in
proportion of the growth pattern at the metastasis
periphery. This seems to be one of the reasons why
the effect of arterial infusion or arterial chemoem-
bolization of metastatic liver cancer is limited.
A few cases of metastatic liver cancer showed a
fibrous capsule and fibrous septa, particularly in
those from colon cancer. Furthermore, microscop-
ic portal venous tumor thrombi were often seen in
metastatic liver cancers in the present study. Indeed,
these are known to be features of hepatocellular
carcinoma, although a few cases of metastatic liver
cancer can also show them.
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