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Gastrointestinal Cancer Metastasis and Lymphogenous Spread: Viewpoint of Animal Models of Lymphatic Obstruction
Introduction
Subjects and Methods
Results
Discussion
Acknowledgments
References
Gastrointestinal Cancer Metastasis and Lymphogenous Spread: Viewpoint of Animal Models of Lymphatic Obstruction
Primary gastrointestinal cancer frequently spreads to the mesentery, omentum and other parts of the peritoneum and these deposits are generally considered to be induced by intraperitoneal seeding from the primary lesion. In this work, we examined the spread of gastrointestinal cancer from the viewpoint of lymphogenous metastasis using a rat model of mesenteric lymph vessel obstruction. With these models, we carried out mesenteric lymphangiography on the fourth and sixth postoperative days (five animals each) to examine morphological changes in the lymph vessels and lymph flow. In model animals with mesenteric lymph vessel obstruction, re-celiotomy, performed on the fourth postoperative day, revealed marked mesenteric edema and enlargement of the mesenteric lymph nodes, suggestive of lymph retention. We also carried out mesenteric lymphangiography and obtained images of extensive mesenteric lymph vessels and reflux of lymph distal to the obstruction point in all five animals. On the sixth postoperative day, we obtained lymphangiographic images of lymphatico-venous communication in the mesentery in all five animals. Thus in animals with lymph vessel obstruction, the lymph flow appeared to change to lymphatico-venous communication or reverse lateral flow. In clinical cases, it is conceivable that lymph retention and reflux of lymph induced by lymph vessel obstruction sometimes play a role in the mechanism of intraperitoneal cancer dissemination and hematogenous metastasis.
Introduction
Generally, cancer metastasis can be classified into three types: lymphogenous metastasis, hematogenous metastasis and peritoneal dissemination. However, the possible existence of links between the three routes has not been clarified. Previously, we recognized lymphatico-venous communication due to obstruction of mesenteric lymph flow and indicated a possible link between lymphogenous and hematogenous metastasis.
Metastasis by peritoneal dissemination is a pattern of spread shown by gastrointestinal cancer and is generally thought to develop as a result of cancer cells being released from the primary lesion into the abdominal cavity and their implantation and proliferation in the milky spots of the greater omentum or peritoneal mesentery. In our previous study, we proposed lymphatico-venous communication due to the complete obstruction model of the mesenteric lymph trunk. Therefore, we have now investigated the spread of gastrointestinal cancer with special reference to lymph retention and also reflux of lymph in the lymph vessels and interstitium.
Subjects and Methods
We established a rat model of mesenteric lymph vessel obstruction using Wistar rats aged 10-12 weeks. Under a microscope (at a magnification of ×4), the mesenteric lymph vessels were divided at the intestinal lymph trunk by ligation and division to interrupt the flow of lymph from the periphery to the intestinal lymph trunk. A rubber sheet was inserted between the stumps of the divided lymph vessels to inhibit lymphatic regeneration and recanalization (1).
The mesenteric artery and vein were preserved and guided through two incised areas of the rubber sheet (Fig. 1). These rat models of mesenteric lymph vessel obstruction underwent re-celiotomy on the fourth and sixth postoperative days (five animals each). The contrast medium Lipiodol was infused continuously at 0.05 ml/min from the mesenteric lymph node distal to the obstruction point. Mesenteric lymphangiography was then performed to assess the resulting morphological changes in the lymphatic system (1). In the control group, mesenteric lymphangiography was carried out (2).
Figure 1. The model of mesenteric lymph vessel obstruction employed. The mesenteric lymph vessels are divided at the intestinal lymph trunk. A rubber sheet is inserted between the stumps of the divided lymph vessels. The mesenteric artery and vein are preserved and are guided through two incised areas of the rubber sheet. Histological investigations were also carried out.
Results
Re-celiotomy on the fourth postoperative day in the model animals with mesenteric lymph vessel obstruction revealed marked edema of the mesentery and enlargement of the mesenteric lymph nodes in all five animals. These signs suggested retention of intestinal lymph.
Lymphangiography revealed extensive mesenteric lymph vessels on the distal side of the obstruction point in all five animals, indicating reflux of the intestinal lymph (Figs 2 and 3). There was collateral flow around the obstruction point in one animal (Fig. 3). Histological examination revealed marked dilatation of the lymphatics in the mesenteric lymph nodes distal to the obstruction, suggesting lymph retention and elevation of endolymphatic pressure (Fig. 4).
Figure 2. Mesenteric lymphangiogram of a model animal with mesenteric lymph vessel obstruction on the fourth postoperative day. The mesenteric lymph vessel shows reflux of intestinal lymph. The arrow shows the obstruction point.
Figure 3. Mesenteric lymphangiogram of a model animal with mesenteric lymph vessel obstruction on the fourth postoperative day. Extensive mesenteric lymph vessels distal to the obstruction point are evident. The arrow shows the obstruction point. There is collateral flow (arrowhead) around the obstruction point.
Figure 4. Histological examination shows marked dilatation of the lymphatics in a mesenteric lymph node distal to the obstruction, suggesting lymph retention and elevation of endolymphatic pressure. Re-celiotomy on the sixth postoperative day revealed edema of the mesentery and slight improvement of lymph node enlargement in comparison with the state on the fourth postoperative day. This suggested the possibility of drainage of the intestinal lymph. By mesenteric lymphangiography, images of the mesenteric vein, portal vein and liver were obtained in all five animals. These images revealed lymphatico-venous communication induced by the mesenteric lymph vessel obstruction (Figs 5 and 6).
Figure 5. Mesenteric lymphangiograms of a model animal with mesenteric lymph vessel obstruction on the sixth postoperative day. The images show the mesenteric vein, portal vein and liver. Lymphatico-venous communication induced by the mesenteric lymph vessel obstruction is evident. The arrow shows the obstruction point.
Figure 6. Mesenteric lymphangiograms of a model animal with mesenteric lymph vessel obstruction on the sixth postoperative day. The arrow shows the obstruction point.
Discussion
Regarding the lymphangiographical findings for the control group without any treatment of the mesenteric lymph vessel, the mesenteric lymph vessel was not extended and the contrast medium flowed promptly to the cysterna chyli and thoracic duct (1-4).
We have previously reported the occurrence of lymphatico-venous communication in experimental models of mesenteric lymph vessel obstruction (3). Since such lymphatico-venous communication induced by lymph retention and elevation of endolymphatic pressure may occur in cases of lymphatic obstruction caused by tumor cells, it seems likely that gastrointestinal cancer cells enter the portal vein via the lymphatic system. In our clinical cases of multiple hepatic metastases of colonic cancer, carbon particles injected into the paracolic lymph nodes were immediately recognized in the lymphocytes of the portal blood (4).
In the present experimental models of mesenteric lymph vessel obstruction, lymphangiography performed on the fourth postoperative day revealed extensive lymph retention and reflux of intestinal lymph. There have been a number of reports of lymphatic obstruction causing lymph retention and reflux. The endothelial cells and basement membranes of lymph vessels are much thinner than those of blood vessels and are often discontinuous, thus increasing the likelihood of cancer cell invasion and exudation into the surrounding interstitial space. Nishidoiet al. (5) investigated cases of gastric cancer combined with microscopic omental metastasis and suggested that the metastasis occurred lymphogenously and hematogenously.
We consider that the intestinal lymph retention and reflux observed in our models of mesenteric lymph vessel obstruction are also applicable to lymphatic obstruction induced by lymphatic invasion and lymph node metastasis of tumor cells. It is well known that in animal models, tumor cells transplanted into the abdominal cavity become implanted and proliferate selectively in the milky spots of the greater omentum (6-9). However, it can also be considered that lymphatic obstruction induced by invasion of tumor cells causes lymph retention and reflux in the lymph vessels and interstitium and hence the resulting lymphatic obstruction might cause hematogenous metastasis, jumping metastasis and peritoneal metastasis via the lymphatic system.
Acknowledgments
This study was presented and received an award for excellence at the 25th Meeting of the Japanese Society for Cancer and Lymph Node Research. The authors thank Dr Kiyoshi Sawai for his valuable assistance in the preparation of this paper.
References
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Last modification: 19 May 1998
Copyright© Japanese Journal of Clinical Oncology, 1998.
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L. Jussila and K. Alitalo
Vascular Growth Factors and Lymphangiogenesis
Physiol Rev,
July 1, 2002;
82(3):
673 - 700.
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