histologic growth patterns of metastatic carcinomas of the liver

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 casesshowed 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 livermetastases, in micrometastases less than 1 mm in diameter a replacement growth pattern waspredominant among metastases from lung, colon and pancreas cancers (69.7%, 79.3% and66.7%, 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 liverover 20 mm in diameter, an expansive growth pattern was predominant, irrespective of thecancer 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 tothe liver, and the frequency of liver metastasis ismuch higher than that of primary liver cancers.1'Eggel classified primary liver cancer as nodulartype, massive type, or diffuse type according to itsgross appearance.2' The histologic patterns oftumor growth of hepatocellular carcinoma attumor-non-tumor boundaries were described byNakashima et al.3) as follows: sinusoidal pattern,cancer cells growing in sinusoids at the boundaryand compressing the liver cell cords; replacementpattern, cancer cells replacing hepatocytes along theliver cell cords, and the cancer cells adhering toeach other; encapsulated pattern, cancer cells grow-ing in an expansive manner and acquiring a fibrouscapsule. Certain metastatic cancers in the liver showsinusoidal growth and a few have surrounding fi-brous capsules." However, little attention has beendirected toward the replacement growth pattern ofmetastatic liver cancer. Furthermore, the difference

Received: May 2, 1995Accepted: August 16, 1995For reprints and all correspondence: Yasuni Nakanuma,Second Department of Pathology, Kanazawa UniversitySchool of Medicine, Kanazawa 920

in predominant growth pattern according to the sizeof metastatic cancers in the liver has not been ad-dressed.

Recent progress in diagnostic modalities has madeit possible to analyze the precise morphologic fea-tures of metastatic liver cancers.4"6' In this- studywe investigated the pathology of metastatic livercancer to elucidate the histologic differences in in-dividual primary sites and to correlate the growthpattern of metastatic liver cancer with the primarysite and the size of the metastatic tumor in orderto improve the interpretation of diagnostic imagingand the planning of treatment for metastatic livercancer.

Materials and Methods

Histologic Specimens

One hundred autopsied livers with metastaticcancers were studied. The background factors aresummarized in Table I. The patients comprised 71men and 29 women, with a mean age of 65.7 <12.3 years. The mean weight of the liver was1729± 942 g. Cancer primary sites were as follows:lung 24; pancreas 21; stomach 18; gallbladder/bileduct 14; colon 13; kidney 3; other cancers 7. Therewas no difference in liver weight or patient age

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HISTOLOGIC GROWTH PATTERNS OF LIVER METASTASES

Table I. Main Clinicopathological Features of Autopsy Cases with Liver Metastases

Primary site

LungPancreasStomachGB/Bile ductColonOthers

GB, gallbladder: *,

Number of cases

242118141310

years (mean±SD); f,

Sex

Male

221915564

gram (mean±SD).

Female

223976

Age of patients *

66.3 ±10.167.4±10.463.3 ±14.969.5 ±10.163.9±15.062.4±12.1

Weight of liver f

1501 ±6121455 ±3772099 ±10781380 ±2452317±15391996±1015

among the primary sites. Each liver was cut into1-cm slices and fixed in 10% buffered formalin.From each liver, we obtained several specimenscontaining various sizes of metastatic tumors, andembedded then in paraffin. Several 5-/mi-thick sec-tions were obtained from each paraffin-embeddedblock and stained with hematoxylin-eosin, Gomori'sreticulin and elastica van Gieson.

Macroscopic Findings

Livers with metastatic tumors were classified bygross macroscopic appearance in accordance withEggel's classification2' into nodular, massive anddiffuse types. Nodular type was subdivided intosolitary, multinodular and fused types. Livers show-ing enlarged portal tracts and linear or small nodu-lar tumors in the vicinity of the portal tractsconsidered to be lymphangiosis carcinomatosa7'8)

were classified as having portal tract-typemetastases.

Microscopic Evaluation

Predominant Sites of Growth: The growth sites ofmetastatic liver cancer were classified into two typesaccording to light microscopic findings: portal tractgrowth, metastatic tumors growing within and/oralong the portal tracts; parenchymal growth,metastatic tumors growing in and/or toward thehepatic parenchyma with no or little portal tractgrowth; intermediate type, including both of theprecious types of growth.

Histologic Growth Patterns: Histologic growth patternat the boundary between the tumor and hepaticparenchyma was classified into five types: sinusoi-dal, replacement and encapsulated growth patterns,which were described in hepatocellular carcinomaby Nakashima et a/.,3) expansive growth patternand unclassified pattern. The histologic features ofthe individual growth patterns are as follows.Sinusoidal growth pattern; tumor cells infiltrate intothe sinusoids at the boundary of the metastasis,and liver cells are left inside the boundary of the

tumor. Replacement growth pattern; tumor cellsgrow within the liver-cell plates, and replacingtumor cells are in continuity with liver cells. In thispattern, compression and destruction of the livercells close to the tumor cells are a little moreprominent than in the replacement growth patternin hepatocellular carcinoma. Expansive gorwth pat-tern; tumor cells compress the liver-cell plates andsinusoids and make the liver cells atrophic. In thispattern, the border of the tumor is somewhat evenand smooth. Encapsulated growth pattern; metastat-ic tumor foci have an enclosing fibrous capsule.The correlation of the ratios of the individualgrowth patterns and the sizes of the metastatictumors were evaluated at each primary site.

Results

Macroscopic Findings

Table II shows the ratios of the macroscopictypes of metastatic liver cancers. Massive type andnodular type comprised 17 (17%) and 73 (73%)cases, respectively. There were no cases showing thediffuse 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 ofthe fused multinodular type (5%). The portal tracttype 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 typewas most frequent. Primary sites of metastatic livercancers showing the portal tract type included 2cases of pancreatic cancer, 2 cases of gastric cancerand 4 cases of gallbladder/bile duct cancer. Four of8 cases were poorly differentiated adenocarcinoma.

Microscopic Evaluation

Predominant Sites of Growth: Cases showingpredominant parenchymal growth were seen in92.3% of colon cancers, 87.5% of lung cancers,66.7% of pancreas cancers, 61.1% of stomach

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Table II. Macroscopic Classification of Liver Metastases

Number (%) of cases

Primary site

LungPancreasStomachGB/Bile ductColonOthers

Number ofcases

242117141310

Massivetype

03(14.3)5(27.8)4(28.6)2(15.4)3(30.0)

Solitary

001(5.6)02(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)01(5.6)02(15.4)0

r

Total

24(100)15(71.4)11(61.2)6(42.8)

11(84.6)6(60.0)

Portal tracttype

02(9.5)2(11.1)4(28.6)00

Invisibletype

01(4.8)0001(10.0)

GB, gallbladder. Diffuse type not found.

cancers, and 35.7% of gallbladder/bile ductcancers. Among liver metastases from colon cancerand lung cancer, the proportion of the cases show-ing parenchymal growth was higher than that forgallbladder/bile duct cancer (iJ<0.05). On the otherhand, cases showing predominant portal tractgrowth were seen in 35.7% of gallbladder/bile ductcancers (Fig. 1), 19.0% of pancreas cancers, 16.7%of stomach cancers, and 4.2% of lung cancers. Inthe ramaining cases: 28.6% of gallbladder/bile ductcancers, 22:2% of stomach cancers, 14.3% of pan-creas cancers, 8.3% of lung cancers and 7.7% ofcolon cancers, both parenchymal growth and por-tal tract growth were seen equally.

Histoiogic Growth Patterns: In small metastases inthe liver less than 1 mm in diameter, a replacementgrowth pattern (Fig. 2) was predominant for lungcancer (69.7%), pancreas cancer (79.3%) and coloncancer (66.7%). In these cases, the proportionshowing an expansive growth pattern increased asthe metastatic tumors grew. In metastases over20 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 sinusoidalgrowth pattern (Fig. 4) was predominant in livermetastases less than 1 mm in diameter from gastriccancer and gallbladder/bile duct cancer (48.5% and66.7%), followed by a replacement growth pattern(39.4% and 26.7%, respectively). The proportionshowing an expansive growth pattern also increasedas the metastatic tumors grew. In these cases, anexpansive growth pattern was also predominant inlesions over 20 mm in diameter (84.6% and47.4%). Table III shows the proportions of the in-dividual growth patterns.

A fibrous capsule around the metastatic livercancer was seen in two cases of colon cancer (Fig.5) and two cases of renal cell cancer. Fibrous septain the metastasis were seen in two cases of coloncancer and one case of small cell lung cancer. Onecase of follicular carcinoma of the thyroid and

Fig. 1. Growth and spread of metastatic carcinoma ofthe 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 oftransitional cell carcinoma of the renal pelvisshowed microscopic intraductal growth.

Discussion

In this study, we classified macroscopically casesof metastatic carcinoma of the liver resembling lym-phangiosis carcinomatosa of the lung7>8) as theportal tract type. In such cases, tumor cells enterthe lymphatics in the portal tracts, spread to the in-terstitium along the lymphatics, spread from thehepatic hilum to the peripheral liver along the por-tal tracts, and linear or small nodular tumors areobserved 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/bileduct cancer, the portal tract type was more fre-quent than in other primary sites. With regard to

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(a)

Fig. 2. Replacement growth pattern, metastasis from adenocarcinoma of the lung, (a) HE and (b) reticulin stain. Metastaticcarcinoma 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 carcinomashows 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 carcinomacells show intrasinusoidal growth and are present between liver-cell plates. M, metastasis.

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Table

Primarv site

Lung

Pancreas

Stomach

GB/bile duct

Colon

III. Proportion of

Size ofmetastasis (mm)

20 <<20< 3< 120 s<20< 3

<I20 <<20< 3< 120 <<20< 3< 120 <<20< 3< 1

Five Types of

Replacing

31.318.940.469.725.037.560.079.3

022.223.539.415.831.628.026.7

7.77.7

12.566.7

Growth Patterns in

Proportion

Expansive

62.575.751.110.650.040.634.30

84.659.352.96.1

47.436.828.0

6.776.984.675.06.7

Relation to

of growth

Sinusoidal

002.1

13.64.23.10

17.27.77.4

20.648.5

000

66.700

12.526.7

i Size of Metastatic

pattern (<%)

Encapsulated

6.300000000000

10.5000

15.4000

Tumor

Unclassified

05.46.46.1

20.818.85.73.47.7

11.12.96.1

26.331.644.0

007.700

Fig. 5. Encapsulated growth pattern. A metastatic car-cinoma from cancer is surrounded by a fibrous capssule.

the predominant sites of growth of metastatic livercancers, prominent portal tract growth abounded inpoorly differentiated adenocarcinoma, particularlymetastases from the stomach, pancreas and gall-blaldder/bile duct. These macro- and microscopicfindings may be related to the anatomical relation-ship between the primary sites and the liver, andthe tendency for the tumor cells to enter the lym-phatic channels. It is considered that these findingsmay be useful for helping to indicate the primarysite.

The present study demonstrated that a replace-ment growth pattern was not rare in metastaticliver cancers. Especially in those from the lung,pancreas and colon, the smaller the size of themetastatic tumor, the higher the frequency of areplacement growth pattern. Compared with thereplacement growth of hepatocellular carcinomanoted by Nakashima et a/.,3) even the tumors grewwithin the liver-cell plates, although destruction andcompression of hepatocytes were more prominentthan in hepatocellular carcinoma. In the cases ofgastric cancer and gallbladder/bile duct cancer, asinusoidal growth pattern was predominant in smallmetastases. Similar to the other primary sites, theproportion of the expansive growth pattern in-creased as the size of the metastases increased. It issuggested that metastatic liver cancers grow in theliver-cell plates and/or sinusoids at first, then thespeed of growth exceeds the rate of hepatocytereplacement by tumor cells or invasion of tumorcells into the sinusoids. Otherwise, the size of themetastatic tumor and growth pattern might be as-sociated with the intensity of adhesion amongtumor cells. That is, tumor cells with strong adhe-sion form large metastatic nodules and show expan-sive growth, and those with weak adhesion formsmall nodules and show a replacement growthpattern.

Small metastatic liver cancers are supplied by sur-rounding hepatic sinusoids, and as the metastatic

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tumor grows, newly formed blood vessels supplythem.9) That is, metastatic liver cancers showing areplacement or sinusoidal growth pattern are possi-bly supplied by sinusoidal blood flow. The switch-ing of the blood supply to metastatic liver cancersis thought to be closely related to the change inproportion of the growth pattern at the metastasisperiphery. This seems to be one of the reasons whythe effect of arterial infusion or arterial chemoem-bolization of metastatic liver cancer is limited.

A few cases of metastatic liver cancer showed afibrous capsule and fibrous septa, particularly inthose from colon cancer. Furthermore, microscop-ic portal venous tumor thrombi were often seen inmetastatic liver cancers in the present study. Indeed,these are known to be features of hepatocellularcarcinoma, although a few cases of metastatic livercancer can also show them.

References

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histologic growth patterns of metastatic carcinomas of the liver

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