What causes metastatic liver cancer? Complete knowledge about metastatic liver cancer

1. Causes of disease

Cancers in almost all organs of the body can metastasize to the liver. Malignant tumors can directly infiltrate surrounding tissues, or invade lymphatic vessels, blood vessels and body cavities. Cancer cells are then transferred to distant sites with lymph, blood and various cavities. The infiltration and metastasis of cancer cells mainly depend on their own malignant biological characteristics and the body's immune status. Cancer cells have ameba-like activity and can autonomously infiltrate and move to surrounding tissues. The decreased adhesion between cancer cells makes them prone to fall off, increasing the chance of metastasis. Cancer cells highly express certain integrins, which may give cancer cells the power to migrate and make it easier for them to penetrate the basement membrane. Certain adhesion molecules in the body help cancer cells to metastasize. Retention in distant organs; increased proteolytic enzyme activity on the surface of cancer cells is also conducive to their infiltration and metastasis. Since most tumor-bearing hosts have low immune function and cannot effectively identify and kill metastatic cancer cells, once cancer cells stay in distant organs, they can release a variety of growth factors and their receptors, such as vascular endothelial growth factor (VEGF), allowing cancer cells to grow autonomously and without restriction. This malignant biological characteristic of cancer cells is related to the genetic information they carry, such as DNA ploidy or stem cell level. Aneuploid cancer cells are more likely to metastasize than diploid cancer cells. Due to its own anatomical and blood supply characteristics, the liver may be more likely to provide a variety of cancer cells with growth space and nutrient sources for retention.

There are four ways that cancers in various parts of the human body metastasize to the liver: portal vein, hepatic artery, lymphatic pathway and direct infiltration.

1. Portal vein metastasis. Malignant tumors in all organs whose blood flows into the portal vein system, such as the lower esophagus, stomach, small intestine, colorectum, pancreas, gallbladder and spleen, can metastasize to the liver through the portal vein. This is an important way for primary cancer to spread to the liver. It has been reported that there is a shunt phenomenon in the portal vein blood flow, that is, the blood flow of the splenic vein and the inferior mesenteric vein mainly enters the left liver, while the blood flow of the superior mesenteric vein mainly flows into the right liver. Tumors in these organs belonging to the portal vein will metastasize to the corresponding parts of the liver due to different blood flow directions, but clinically the shunt of this tumor metastasis is not obvious, and scattered metastasis to the whole liver is more common. Cancers in other parts such as the uterus, ovaries, prostate, bladder and retroperitoneal tissues can also metastasize to the liver through the systemic veins or the anastomotic branches of the portal vein; they can also metastasize to the liver because the tumors in these parts grow and invade the organs of the portal vein system; or they can first metastasize from the systemic veins to the lungs, and then from the lungs to the whole body circulation to the liver.

2. Hepatic artery metastasis Any cancer that spreads through the blood can metastasize to the liver through the hepatic artery. For example, malignant tumors in the lungs, kidneys, breasts, adrenal glands, thyroid glands, testicles, ovaries, nasopharyngeal, skin and eyes can spread to the liver through the hepatic artery. Metastasis to the liver is also common.

3. Lymphatic metastasis: Pelvic or retroperitoneal cancer can metastasize to the para-aortic and retroperitoneal lymph nodes via the lymphatic vessels, and then flow back to the liver. Digestive tract cancer can also metastasize to the liver via the hilar lymph nodes along the lymphatic vessels. Breast cancer or lung cancer can also metastasize to the liver via the mediastinal lymph nodes, but this method of metastasis is less common. Clinically, it is more common for gallbladder cancer to metastasize to the liver along the lymphatic vessels of the gallbladder fossa.

4. Cancers that directly infiltrate organs adjacent to the liver, such as gastric cancer, transverse colon cancer, gallbladder cancer, and pancreatic cancer, can spread to the liver due to direct infiltration of cancer cells due to adhesion between the cancer and the liver. Cancer of the right kidney and adrenal gland can also directly invade the liver.

2. Pathogenesis

The liver is an organ extremely suitable for the growth of tumor cells, among which gastrointestinal tumors are most likely to metastasize to the liver. This is related to the fact that the liver receives blood perfusion from the portal vein system. As for how the liver becomes the organ where metastatic cancer most often occurs, it is by no means only due to the rich blood and lymphatic drainage. Its internal mechanism is not yet clear. The metastasis of cancer cells is a complex multi-step process, including the shedding of primary cancer cells, survival after passing through the vascular wall and entering the blood circulation or lymphatic system, selection of implantation tissue or organ, growth and division of cancer cells after implantation to form metastatic foci, etc. The fine structure of the liver may also affect the occurrence of tumors. The blood flow of the liver passes through the hepatic sinusoids, and the sinusoidal endothelial cells and Kupffer cells play a role in retaining cancer cells. The rich dual blood supply of the liver also helps metastatic cancer cell emboli obtain nutrition supply, and the hepatic sinusoids Endothelial cells are characterized by having pores of different sizes; there are Kupffer cells in the liver sinusoids, which are good at capturing granular substances in the liver sinusoid blood flow and blocking the path of tumor cells in the blood flow. Platelets accompanying Kupffer cells are more helpful in capturing tumor cells. If tumor cells want to survive, they must pass through the liver sinusoid endothelial cell layer to reach the Disse gap, otherwise they will be surrounded and destroyed by Kupffer cells. The Disse gap provides excellent growth conditions for tumor cells, with both nutrient-rich filtrate from the liver sinusoid blood flow and no resistance and interference from other cells. Therefore, the development of metastatic lesions in the liver is often much faster than that in other parts of the body. When liver metastasis occurs, the patient's life is often endangered first due to liver metastasis. .

It is now believed that after about 20 doublings, tumor cells can reach a diameter of 1 mm and a cell count of about 1 million, and then they have the ability to metastasize. At this time, the tumor nodules are still difficult to be found by modern advanced imaging examinations. It can be seen that it is very difficult to find a true carcinoma in situ, especially in an organ as deep as the liver. When the tumor nodules have doubled 20 to 80 times, they may be found by modern examination methods. Therefore, when the tumor nodules are discovered early, the tumor has actually existed for several months to several years, and during this period of time the tumor has the ability to metastasize.

Animal experiments suggest that 4 million tumor cells can fall off from every gram of tumor tissue every 24 hours, which can become the source of metastasis. However, 90% of these tumor cells quickly disappear in the circulation, and more than 99% will die quickly. Therefore, metastasis is not always effective. It depends on the body's defense capabilities, local conditions, biological characteristics of tumor cells, and many other factors. Most of the tumor cells that fall off into the circulation are scattered, and less than 0.1% may aggregate to form cell clumps or tumor thrombi. The latter have a much higher chance of establishing metastatic foci in new locations than scattered cells. When establishing metastatic foci, tumor cells need to pass through the microvascular endothelium to the perivascular area. When tumor nodules reach 1 to 3 mm, they must establish their own vascular supply to maintain the need for continuous proliferation. Moreover, metastatic foci can become a new source of metastasis. If there is no sufficient blood circulation, tumor cells can only rely on the diffusion of nutrients to maintain their survival. Then, tumor cells will achieve a balance between reproduction and death, and the tumor will maintain a size of 1 to 3 mm without increasing.

The metastatic site of tumor cells is the capillary network or lymph nodes that drain the area, so the first site of visceral tumor metastasis is the liver, but some metastatic lesions remain "latent" and do not develop into large metastases, which may be related to the latency of tumor cells; cell latency refers to the metastatic tumor cells being in the G1 phase of cell division, but maintaining their ability to divide subsequently, which can explain why metastatic lesions appear clinically many years after the primary tumor is resected. Many experiments have shown that surgery, hormonal effects, and impaired immune function can activate and grow latent metastatic tumor cells; clinically, some stimuli such as radiation, surgical trauma, pregnancy, stress, and infection can also stimulate the activation of latent tumor cells and grow them into large tumors. The liver receives dual blood supply from the portal vein and the hepatic artery. Liver metastasis can come from the portal vein circulation and the systemic circulation, that is, tumor cells enter the systemic circulation through the pulmonary capillaries. Liver metastasis Studies on the blood supply of tumors suggest that when metastatic tumors grow and enlarge, new blood vessels are generated, while existing blood vessels or normal blood vessels are blocked. In the early stage of metastasis, when the tumor is less than 1mm, nutrition mainly comes from the diffusion of peripheral circulation; when the tumor reaches 1-3mm, arteries, portal veins, and mixed capillary networks are formed around the tumor; when the tumor grows further, the blood supply becomes complicated, and about 90% of the main blood supply comes from the hepatic artery; therefore, some people propose to use hepatic artery ligation to treat metastatic liver cancer; once the tumor volume reaches 1.5-3.0cm, the blood supply is also more complicated. From imaging observations such as angiography, blood flow still mainly comes from the hepatic artery. Due to the duality of liver blood supply, some metastatic tumors in the liver may be displayed as high-density shadows in arterial CT scans, while others may not be displayed; similarly, similar effects can be seen in portal vein CT scans. .

The metastatic cancer nodules of the liver vary in size and number. They may be isolated 1 to 2 nodules, but most are diffuse multiple nodules that can be scattered in one lobe of the liver or the entire liver. The cancer nodules are mostly grayish white in appearance and hard in texture. The center of the nodule is often sunken due to necrosis, and there is a clear boundary between the nodule and the surrounding liver tissue. The capsule is mostly intact. The cancer is mostly located on the periphery of the liver, but some are hidden deep in the liver parenchyma.

The pathological tissue morphology of secondary liver cancer is similar to that of its primary cancer. For example, the liver metastatic cancer from gastric adenocarcinoma or colon adenocarcinoma can show adenocarcinoma structure in its tissue; the tumor tissue from eye melanoma is brown or black because it contains melanin, but this is not the case in some cases because the tumor cells are too poorly differentiated to identify the characteristics of the primary cancer.

The primary cancer of secondary cancer that metastasizes to the liver through the bloodstream may be very small and undetectable, but the metastatic cancer to the liver grows very quickly and invades the entire liver. Unlike primary hepatocellular carcinoma, metastatic cancer to the liver rarely occurs with cirrhosis, and does not invade the portal vein or form cancer thrombi.