445
Atherosclerosis, 32 (1979) 445-450 0 Elsevier/North-Holland Scientific Publishers, Ltd.
THE ARTERIAL
WALL IN MALIGNANT
DISEASE
F.H. SEMS Women’s College Hospital, 76 Grenville Street,’ Toronto, M5S IB2, Ontario (Canada) (Received 14 August, 1978) (Revised, received 6 November, 1978) (Accepted 20 November, 1978)
Summary The intimal thickening of arteries present in 95 resected specimens of carcinoma of the colon was studied, using sections from the tumour area and from adjacent normal bowel. Arteries from the tumour area showed a very significant increase in intimal thickening as compared with the controls. It is suggested that the local factor associated with the turnour area is an impaired drainage of macromolecules from the intimal’compartment of the arteries due to obstruction of the lymphatic channels of the surrounding interstitial tissue by tumour cells and fibrosis. Key
words:
Arterioclerosis Malignant disease
Atherosclerosis
-
Intimal thickening
- Macromolecules
-
Introduction Current views of the aetiology of arteriosclerosis have been reviewed in many recent publications [l-8], and in these surveys the mechanism of intimal thickening has been discussed. Most of these theories postulate endothelial injury as the initiating step, followed by smooth muscle jmesenchymal) proliferation and plaque formation [2,4,5,8]. More recently Benditt and others have advanced the concept of an adenomatous proliferation of the smooth , muscle cells of the media [ 71. Observations on human pathological material present many puzzling facts apparently inconsistent with any theory depending on such general features as the endothelial surface, or components of the homogeneous circulating tilood. It is difficult for example, to explain how in human material one artery will be affected, but a neighbouring vessel of equivalent size will remain normal in histological appearance. An alternative mechanism of intimal thickening in arteriosclerosis already out-
446
lined [9], postulates that the environment of the arterial wall is more important in causing intimal thickening than events within the lumen of the vessel. It suggests that it is the difficulty of removal of macromolecules (principally protein) from the intimal compartment which brings about persistent oedema of the intima and the proliferation of smooth muscle cells from the media into the oedematous intimal space. Intimal thickening occurs readily in areas involved in an inflammatory process, where increased permeability of the endothelium and overloading of the lymphatic drainage of the surrounding interstitial tissue is seen. A further test of the hypothesis would be provided by blockade of the lymphatic ducts of. the connective tissue surrounding arterial walls. This should cause a significant increase in intimal thickening in the affected vessels. Such an experiment of nature is readily available. In malignant disease, obstruction of lymphatics by groups of tumour cells commonly occurs. It might be predicted therefore, that arteries involved in advanced malignancy might show an unusual degree of intimal thickening; that this would be greater than expected from the patient’s age, and different from that of other neighbouring vessels in the same subject. This study is a survey of the arteries in 95 unselected resection specimens of carcinoma of the colon. Material and Methods The material examined comprised tissue from 95 resection specimens of carcinoma of the colon, collected without selection during the last two and a half years. The ages of the patients ranged from 28 to 92 yr. In each case, sections were taken from the tumour area, and also from the normal colon proximal and distal to the tumour area. Since intimal thickening is a patchy process involving some vessels or portions of a vessel and not others, measurements of the 3 vessels showing the maximum intimal thickening were made, using the sections of both tumour and control areas of each specimen. The arteries of the tumour area examined were either surrounded by tumour, or were adjacent to an area of tumour cells. Actual invasion of the arterial wall by tumour was a reason for rejection of that particular artery from the series. The intimal thickness for each ‘of these vessels was assessed visually as a proportion of the thickness of the media, the figures so obtained being examined statistically as described below. There is evidence [9] that the magnitude of the intimal thickening increases with increasing thickness of the media, so that measurement of the intimal thickness as a fraction of that media, tended to minimize the effect of difference in size of the arteries examined. Also this procedure minimized artefactual changes such as shrinkage during the preparation of the histological sections. Results The distribution of arteries having various degrees of intimal thickening is shown for tumour and control vessels in Fig. 1. Only arteries of diameter greater than 150 pm were used for the statistics. It can be seen that greater numbers of
447
COMPARISON
CARCINOMA OF THE COLON OF TUMOUR AND CONTROL P=~o.wl
CONTROL
ARTERIES
(X21861)
VESSELS
n=209 x.1.9
.E loo2 6
80-
$ f 3
TUMOUA
OL
VESSELS
n.222
60-
Z. 6.7
0
2
4
8
810
0 Ratio
Fig. 1. The distribution and control areas.
of arteries
2
4
8
8 10 12 14 16 18 20
lntimal Thickness x 10 Thickness of Media
having various
degrees
of intimel thickening
in the sections
of tumour
The mean tumour vessels than controls show significant intimal thickening. of the media for the control vessels (n = ratio of intimal thickness/thickness 209) was 0.19, while that for the tumour arteries (n = 222) was 0.67. A x2 test applied to the two series shows that the chance that the two groups of numbers belong to the same population is very much less than 1 in 1000. The correlation between intimal thickening and the age of the patient is 0.22 for the tumour arteries, and 0.37 for the control vessels. Insignificant intimal thickening was seen in 60% of the control arteries, but only in 18% of the tumour vessels. It is thus clear that some factor other than age is causing a significant increase in the intimal thickening of the tumour vessels. An example of advanced intimal thickening of an artery surrounded by tumour is seen in Fig. 2. Similar changes can be seen readily in other organs showing a heavy tumour infiltration. For example, in carcinoma of the lung (Fig. 3), a finding reported in 1965 by Wagenvoort [lo]. If tumour tissue is present only on one aspect of an arterial wall, there is frequently thickening of that portion of the intima only. The thickened intima which develops in an arterial wall surrounded by tumour is associated with a variable degree of formation of collagenous and elastic tissue similar to that of vessels showing typical arteriosclerosis (Fig. 4). In the smaller vessels the intimal thickening is composed almost entirely of smooth muscle (mesenchymal) cells. In the larger vessels there is more col-
Fig. 2. An example x 100. Fig. 3. Intimal H&E. X 100.
of advanced
thickening
intimal
thickening
in a pulmonary
artery
of an artery
surrounded
Fig. 4. The thickened intima of an art&y surrounded and elastic tissue in the tntimal.zone. The histological in other areas. X 100.
sunounded
by infiltrating
by an infiltrating
by tumour appearance
tumour.
carcinoma
H&E.
of the lung.
stained by Van Gieson to show collagen is similar to human arteriosclerosis seen
lagenous and elastic tissue as isi seen in arteriosclerotic in older lesions.
thickening;,
particularly
Discussion The intimal thickening in arteries surrounded by tumour:has essentially the same histological features as arteriosclerosis seen elsewhere in human material. It is patchy in its incidence. One vessel will be affected while a neighbouring artery will not show significant intimal thickening. Different portions of the same vessel will show marked differences in the degree of intimal thickening, Ed this is often asymmetrical in its orientation, sometimes associated with the presence of tumour tissue.on one aspect only of the vessel. There is therefore good reason to suppose that the presence of the tumour has introduced a local factor promoting intimal thickening, and that this is of the same-type as is seen in human arterial disease. 0,: The .csncept.,that intimal oedwa is associated with the formation of the atheE
Atherosclerosis, 32 (1979) 445-450 0 Elsevier/North-Holland Scientific Publishers, Ltd.
THE ARTERIAL
WALL IN MALIGNANT
DISEASE
F.H. SEMS Women’s College Hospital, 76 Grenville Street,’ Toronto, M5S IB2, Ontario (Canada) (Received 14 August, 1978) (Revised, received 6 November, 1978) (Accepted 20 November, 1978)
Summary The intimal thickening of arteries present in 95 resected specimens of carcinoma of the colon was studied, using sections from the tumour area and from adjacent normal bowel. Arteries from the tumour area showed a very significant increase in intimal thickening as compared with the controls. It is suggested that the local factor associated with the turnour area is an impaired drainage of macromolecules from the intimal’compartment of the arteries due to obstruction of the lymphatic channels of the surrounding interstitial tissue by tumour cells and fibrosis. Key
words:
Arterioclerosis Malignant disease
Atherosclerosis
-
Intimal thickening
- Macromolecules
-
Introduction Current views of the aetiology of arteriosclerosis have been reviewed in many recent publications [l-8], and in these surveys the mechanism of intimal thickening has been discussed. Most of these theories postulate endothelial injury as the initiating step, followed by smooth muscle jmesenchymal) proliferation and plaque formation [2,4,5,8]. More recently Benditt and others have advanced the concept of an adenomatous proliferation of the smooth , muscle cells of the media [ 71. Observations on human pathological material present many puzzling facts apparently inconsistent with any theory depending on such general features as the endothelial surface, or components of the homogeneous circulating tilood. It is difficult for example, to explain how in human material one artery will be affected, but a neighbouring vessel of equivalent size will remain normal in histological appearance. An alternative mechanism of intimal thickening in arteriosclerosis already out-
446
lined [9], postulates that the environment of the arterial wall is more important in causing intimal thickening than events within the lumen of the vessel. It suggests that it is the difficulty of removal of macromolecules (principally protein) from the intimal compartment which brings about persistent oedema of the intima and the proliferation of smooth muscle cells from the media into the oedematous intimal space. Intimal thickening occurs readily in areas involved in an inflammatory process, where increased permeability of the endothelium and overloading of the lymphatic drainage of the surrounding interstitial tissue is seen. A further test of the hypothesis would be provided by blockade of the lymphatic ducts of. the connective tissue surrounding arterial walls. This should cause a significant increase in intimal thickening in the affected vessels. Such an experiment of nature is readily available. In malignant disease, obstruction of lymphatics by groups of tumour cells commonly occurs. It might be predicted therefore, that arteries involved in advanced malignancy might show an unusual degree of intimal thickening; that this would be greater than expected from the patient’s age, and different from that of other neighbouring vessels in the same subject. This study is a survey of the arteries in 95 unselected resection specimens of carcinoma of the colon. Material and Methods The material examined comprised tissue from 95 resection specimens of carcinoma of the colon, collected without selection during the last two and a half years. The ages of the patients ranged from 28 to 92 yr. In each case, sections were taken from the tumour area, and also from the normal colon proximal and distal to the tumour area. Since intimal thickening is a patchy process involving some vessels or portions of a vessel and not others, measurements of the 3 vessels showing the maximum intimal thickening were made, using the sections of both tumour and control areas of each specimen. The arteries of the tumour area examined were either surrounded by tumour, or were adjacent to an area of tumour cells. Actual invasion of the arterial wall by tumour was a reason for rejection of that particular artery from the series. The intimal thickness for each ‘of these vessels was assessed visually as a proportion of the thickness of the media, the figures so obtained being examined statistically as described below. There is evidence [9] that the magnitude of the intimal thickening increases with increasing thickness of the media, so that measurement of the intimal thickness as a fraction of that media, tended to minimize the effect of difference in size of the arteries examined. Also this procedure minimized artefactual changes such as shrinkage during the preparation of the histological sections. Results The distribution of arteries having various degrees of intimal thickening is shown for tumour and control vessels in Fig. 1. Only arteries of diameter greater than 150 pm were used for the statistics. It can be seen that greater numbers of
447
COMPARISON
CARCINOMA OF THE COLON OF TUMOUR AND CONTROL P=~o.wl
CONTROL
ARTERIES
(X21861)
VESSELS
n=209 x.1.9
.E loo2 6
80-
$ f 3
TUMOUA
OL
VESSELS
n.222
60-
Z. 6.7
0
2
4
8
810
0 Ratio
Fig. 1. The distribution and control areas.
of arteries
2
4
8
8 10 12 14 16 18 20
lntimal Thickness x 10 Thickness of Media
having various
degrees
of intimel thickening
in the sections
of tumour
The mean tumour vessels than controls show significant intimal thickening. of the media for the control vessels (n = ratio of intimal thickness/thickness 209) was 0.19, while that for the tumour arteries (n = 222) was 0.67. A x2 test applied to the two series shows that the chance that the two groups of numbers belong to the same population is very much less than 1 in 1000. The correlation between intimal thickening and the age of the patient is 0.22 for the tumour arteries, and 0.37 for the control vessels. Insignificant intimal thickening was seen in 60% of the control arteries, but only in 18% of the tumour vessels. It is thus clear that some factor other than age is causing a significant increase in the intimal thickening of the tumour vessels. An example of advanced intimal thickening of an artery surrounded by tumour is seen in Fig. 2. Similar changes can be seen readily in other organs showing a heavy tumour infiltration. For example, in carcinoma of the lung (Fig. 3), a finding reported in 1965 by Wagenvoort [lo]. If tumour tissue is present only on one aspect of an arterial wall, there is frequently thickening of that portion of the intima only. The thickened intima which develops in an arterial wall surrounded by tumour is associated with a variable degree of formation of collagenous and elastic tissue similar to that of vessels showing typical arteriosclerosis (Fig. 4). In the smaller vessels the intimal thickening is composed almost entirely of smooth muscle (mesenchymal) cells. In the larger vessels there is more col-
Fig. 2. An example x 100. Fig. 3. Intimal H&E. X 100.
of advanced
thickening
intimal
thickening
in a pulmonary
artery
of an artery
surrounded
Fig. 4. The thickened intima of an art&y surrounded and elastic tissue in the tntimal.zone. The histological in other areas. X 100.
sunounded
by infiltrating
by an infiltrating
by tumour appearance
tumour.
carcinoma
H&E.
of the lung.
stained by Van Gieson to show collagen is similar to human arteriosclerosis seen
lagenous and elastic tissue as isi seen in arteriosclerotic in older lesions.
thickening;,
particularly
Discussion The intimal thickening in arteries surrounded by tumour:has essentially the same histological features as arteriosclerosis seen elsewhere in human material. It is patchy in its incidence. One vessel will be affected while a neighbouring artery will not show significant intimal thickening. Different portions of the same vessel will show marked differences in the degree of intimal thickening, Ed this is often asymmetrical in its orientation, sometimes associated with the presence of tumour tissue.on one aspect only of the vessel. There is therefore good reason to suppose that the presence of the tumour has introduced a local factor promoting intimal thickening, and that this is of the same-type as is seen in human arterial disease. 0,: The .csncept.,that intimal oedwa is associated with the formation of the atheE
