I. Disease Overview
Liver metastases (ML), also known as metastatic liver cancer or secondary liver cancer, are caused by the metastatic growth of malignant tumors from various organs throughout the body to the liver, including metastases, metastatic sarcoma and leukemia or lymphoma infiltration.
The liver is the largest substantial organ in the body, which is extremely suitable for the growth of tumor cells and is one of the organs most prone to the formation of metastatic tumors. The infiltration and metastasis of cancer cells mainly depend on their own malignant biological characteristics and the immune status of the body. Cancer cells have amoeba-like activity and can infiltrate and move to surrounding tissues autonomously; the adhesion between cancer cells is reduced, which makes them easy to shed and increases the chance of metastasis; the high expression of certain integrins in cancer cells may give cancer cells the power to migrate and make them penetrate basement membrane easily; some adhesion molecules in the body help cancer cells to stay in metastatic organs; the increase of protein hydrolase activity on the surface of cancer cells also facilitates their infiltration. The increase of protein hydrolase activity on the surface of cancer cells also facilitates their infiltration and metastasis. Since most tumor-bearing hosts are immunocompromised, they cannot effectively identify and kill metastatic cancer cells, and once cancer cells stay in distant organs, they can release various growth factors and their receptors to make cancer cells grow autonomously and unrestrictedly. Heteroploid cancer cells are more likely to metastasize than diploid cancer cells.
The rich space between the endothelial cells of liver sinusoids without basement membrane coverage provides powerful conditions for the stay and growth of circulating cancer cells. The rich dual blood supply of liver helps metastatic cancer cell emboli to obtain nutritional supply, and the tumor cells entering the liver by blood flow, after successfully escaping the fate of Kupffer cell encirclement and elimination, cross the endothelial cell layer of liver sinusoids to reach the Disse gap, and the Disse The Disse gap provides excellent growth conditions for tumor cells, where there is both nutrient-rich filtrate from the hepatic sinusoidal blood flow and no other cellular opposition or interference, and thus metastases in the liver tend to develop much more rapidly than those in other sites. The liver receives blood perfusion from the portal venous system; therefore, gastrointestinal tumors are most likely to develop liver metastases. When liver metastasis occurs, the patient’s life is often endangered by liver metastasis firstly. With the current clinical diagnosis technology and imaging level, those with liver metastasis are already in advanced stage.
1.Epidemiology of liver metastases The incidence of liver metastases in Europe and America is much higher than that of primary liver cancer (about 20:1), and the incidence of both in China is relatively similar. Liver metastasis occurs in 30%-50% of malignant tumors, and cancer of almost all organs of the body can be metastasized to the liver. According to clinical data, about 2/3 of secondary hepatocellular carcinomas come from intra-abdominal tumors, in the order of stomach, pancreas, colorectum, gallbladder, kidney and ovary; the remaining 1/3 mostly come from lung, nasopharynx, breast and soft tissue, etc., but there are still some clinical cases with unknown primary foci. The incidence of metastases was 73% (383/525) in colorectal cancer, 56% (158/282) in gastric cancer, 79% (148/187) in pancreatic cancer, 66% (643/974) in breast cancer, 50% (593/1186) in lung cancer, 43% (200/46) in uterine tumors, 53% (177/334) in ovarian tumors, 58% (160/276) in cutaneous tumors, and 58% (160/276) in hepatic tumors. 58% (160/276) for skin tumors.
2. Metastatic pathways of liver metastases There are three ways for tumors to metastasize to the liver.
(1) Direct spread: cancer of adjacent organs of liver such as stomach, gallbladder, pancreas, transverse colon and duodenum, right kidney, malignant tumor of right adrenal gland directly invade the liver.
(2) Lymphatic metastasis: carcinoma of digestive system metastasizes to liver retrogradely through lymph nodes of hepatic hilar via lymphatics, carcinoma of pelvis or retroperitoneum flows backward to liver, carcinoma of breast and lung metastasizes to liver through mediastinal lymphatics, carcinoma of gallbladder metastasizes to liver along lymphatics of gallbladder fossa.
(3) Hematogenous metastasis
(1) Transhepatic arterial metastasis: any hematogenous cancer can metastasize to the liver via hepatic artery, such as malignant tumors of lung, breast, thyroid, kidney, adrenal gland, skin and melanoma.
(2) Trans-portal metastasis: all malignant tumors in organs whose blood flows into the portal vein system, such as lower esophagus, stomach, small intestine, colon, rectum, gallbladder, pancreas and spleen, can metastasize to the liver via portal vein. Other parts such as uterus, ovary, prostate, bladder and retroperitoneal tumor can also metastasize to liver through the anastomotic branch of body vein and portal vein, or the tumor of these parts can invade the organs of portal vein system first and then metastasize to liver through portal vein.
3.Clinical manifestation of liver metastases The clinical manifestation of liver metastases is very similar to that of primary liver cancer. Since liver metastases do not combine with cirrhosis, their clinical symptoms are slightly inferior to that of primary liver cancer, with slow development and less complications. In the early stage, there are no obvious symptoms and signs, or they are hidden by the primary tumor, and most of them are detected by imaging examination. Once clinical manifestations are present, the metastases are often larger or more numerous. The common symptoms of patients in the middle and late stage include: non-specific manifestations, such as weight loss, weakness, poor performance, fever, etc.; local manifestations of liver, such as discomfort, pain, liver size, hardening and tenderness; some patients may have splenomegaly or ascites. In the absence of biliary obstruction, most patients have no jaundice or only mild jaundice. In the end stage of the disease, liver enlargement, ascites, jaundice, and cachexia are progressively aggravated.
More than 90% of patients with liver metastases have AFP <25 μg/L. A few liver metastases from the stomach, esophagus, pancreas and ovaries may have low positive AFP, usually <100 μg/L. Subclinical liver metastases often have no enzymatic abnormalities. ALP is of great value in the diagnosis of liver metastases, and CEA is of great significance in the detection of liver metastases from gastrointestinal malignancies.
Pathological changes
Liver metastases are the most common tumors in the liver. Clinical attention should be paid to exclude metastatic tumors when confirming the diagnosis of primary liver cancer. The pathological histomorphology of liver metastases is similar to that of their primary carcinoma, which is easier to identify; while liver metastases of adenocarcinoma of the stomach and intestine are sometimes difficult to distinguish from bile duct cell carcinoma; if the tumor cells are undifferentiated or dedifferentiated, it is more difficult to determine their origin if there is no history of primary carcinoma. Liver metastases may appear as isolated 1-2 nodules, but they are mostly multiple, scattered or diffuse nodules. The nodules may vary in size and number and may be scattered throughout one lobe of the liver or the whole liver, and some nodules may fuse to form large masses. Sometimes metastases develop first as a large nodule or even as a mass somewhere in the liver, and then the latter spreads through the portal branches of the liver to form multiple nodules.
III. Imaging manifestations
There are many imaging methods for liver lesions, which play an important role and position in the diagnosis of liver metastases. At present, the correct diagnosis and efficacy assessment of hepatic neoplastic lesions depend to a great extent on imaging examinations.
(A) Ultrasound examination
The sonogram of metastatic liver cancer from different tissues and organs can have different characteristics, which can be helpful to find the primary cancer clinically.
The morphology of cancer foci can be divided into
①Nodular type: most of the tumor nodules are less than 3cm, round or round-like, single or multiple, and multiple metastatic nodules may fuse to form “grape bunch” sign or “cluster sign”;
(2) Macroscopic type: the diameter of tumor foci are mostly between 5-10cm, mainly single, irregular, and often distort the morphological structure of the liver;
(3) Infiltrative type: ultrasound shows that the primary cancer and the adjacent liver tissues are compressed and infiltrated, and the margins of the lesions in the liver are irregular and blurred.
The internal echogenicity of tumor foci can be classified as follows
(1) Strong echogenic type: the tumor foci have clear boundaries, hypoechoic halo around the periphery, and uneven patchy strong echogenicity inside, with weak posterior echogenicity.
(2) Hypoechoic type: the internal hypoechoic tumor foci with clear borders and halo signs.
(3) “Bull’s-eye” echogenic type: A round tumor nodule with clear borders has uniform strong echogenicity or isoechogenicity inside, surrounded by hypoechoic bands, and the inner and outer edges of the dark ring are clearly demarcated, which is called “bull’s-eye sign”. In some tumor nodules, the central necrotic area liquefies into a liquid dark area, which is surrounded by a strong echogenic area in the middle and a hypoechoic band at the edge, forming a three-layer “target ring sign”.
④Mixed type: cystic solid tumors with large components, mostly with ring-like strong echogenicity and irregular anechoic or hypoechoic areas in the middle due to tumor degeneration, necrosis and liquefaction.
⑤ Echo-free type or cystic type: mostly seen in cystic adenocarcinoma liver metastasis. The tumor foci are cystic echogenic with thick and rough walls, and the septa are irregularly thickened in those with multiple atria. (6) Calcified type: The tumor foci are strongly echogenic with posterior acoustic shadow.
When the liver is diffusely infiltrated by metastases, the ultrasound may show ① “wormy type”: the whole liver shows extensive uneven faint patchy abnormal echogenicity; ② “corn type”: the liver is large and deformed, and dense and uniform fine dots are diffusely distributed; ③ “grayish type”: lymphatic-reticular malignant tumor occurs when diffuse cellular infiltration in the liver occurs, and the whole liver is hypoechoic.
2.Color Doppler and spectral Doppler performance In larger (>3cm) liver metastases, color flow of varying lengths in strips or short rods can be seen inside or at the inner edge of the tumor foci, and spectral Doppler detects arterial blood flow or mixed arterial and venous blood flow spectrum, which is called intra-tumor arterial blood flow type. Arterial blood flow and portal venous blood flow can be detected within the ring-shaped halo around the smaller (<3cm) liver metastases, which shows semi-circular or arc-shaped colorful low-velocity blood flow signal, called extra-tumor circumferential blood flow type.
(ii) CT examination.
CT is one of the most useful methods to diagnose liver metastases. The accuracy of CT diagnosis mainly depends on the type of primary tumor and the scanning technique used, and the diagnostic accuracy of dynamic rapid enhancement scan for liver metastases can reach 72.5%-100%. For lesions less than 2cm or 1cm in diameter, the sensitivity of CT with delayed high-dose CT combined with dynamic contrast enhancement and angiography can reach 82%-87%. The sensitivity of spiral CT scan for the detection of metastases smaller than 10 mm can reach 68%, and the detection rate of metastases above 10 mm can reach 98%.
(1) CT scan performance: liver metastases occurring on the basis of normal liver tissue have lower density than the liver parenchyma on flat scan and show multiple, nodular hypodense foci, and are characterized by central round or irregular-shaped necrosis visible in the lesions. The density of metastases in fatty liver can be higher, equal or lower than that of liver parenchyma, which can be easily missed on plain scan. They are dense when there is fresh bleeding or calcification within the tumor.
(2) Enhancement scan: Enhancement performance depends on the blood supply of the tumor itself and the enhancement scan modality. Most liver metastases are hypovascular and therefore remain lower in density than the surrounding liver parenchyma on enhancement scan. Metastases that occur on the background of diffuse fatty infiltration of the liver show up on enhancement scan because the density of the metastases is higher than that of the fatty liver. CT enhancement of liver metastases may show the following.
①Enhancement at the edge of the lesion
②Uniform or heterogeneous enhancement of the whole tumor foci
(3) In the early stage (arterial stage) of dynamic enhancement scan, the enhancement is significant and the density is higher than that of normal liver tissue; in the case of metastases with rich blood supply, the enhancement can be similar in phase and intensity to that of liver parenchyma;
In the delayed phase of dynamic enhancement scan of liver metastases, the foci are hypointense;
(5) Cystic changes: cystic adenocarcinoma metastases in the liver often show cystic changes, and the density of necrosis in the center of large lesions is lower than that in the margins, which becomes more clear after enhancement;
(6) Circumferential enhancement at the edge of tumor foci: Circumferential enhancement with higher density than normal liver in both arterial and portal vein phases, and multiple nodules occurring in the liver, are important features for CT diagnosis of liver metastases;
(⑦) Large metastases may invade local blood vessels, but it is less common to see large intrabranch such as portal vein cancer thrombosis.
(8) The edge of the lesion represents the “halo sign” of pseudo-envelope.
(C) MRI examination
Among various imaging methods, MRI is the most sensitive for detecting liver metastases. Most of the T1WI tumors show moderate low signal, and the enhancement scan shows mild enhancement. They are moderately high signal on T2WI. MRI signal intensity is heterogeneous due to changes such as necrosis, cystic degeneration, hemorrhage, fatty infiltration, atrophy, fibrosis, and calcification, which often occur within the tumor.
The typical manifestations of liver metastases are.
(1) The so-called “target sign” or “bull’s-eye sign” with slightly high signal at the edge of the lesion on T1WI and low signal inside. The central part of the tumor has a small circular or lamellar pattern of uniform or heterogeneous high signal on T2WI, surrounded by an inner halo of high or low signal compared to normal liver parenchyma, or an outer halo of higher signal than normal liver parenchyma outside the inner halo. Wall nodules and strengthening edges are common on enhancement scans.
The peri-tumor “halo sign” can be formed when the peri-tumor edema zone is a slightly high signal ring, or when the center of the tumor is low signal with coagulated necrotic signal and surrounded by the surviving tumor tissue with high signal. When the tumor foci are completely liquefied and necrotic or cystic, the T2WI shows obvious high signal like a light bulb, which is called the “light bulb sign”. Some metastases with rich blood supply, such as smooth muscle sarcoma, pheochromocytoma, endocrine tumor, lung cancer, kidney cancer, etc., may also show significant high signal on T2WI because of their vascular components. Malignant melanoma liver metastases may show T1WI high signal and T2WI low signal.
Other causes of T1WI high signal in tumor foci include.
① Fresh bleeding within the metastases ;
② Liver metastases from mucus-secreting tumors such as ovarian cancer, gastric cancer, pancreatic cystic adenocarcinoma and carcinoid tumors, where the tumor cells are rich in mucus. Liver metastases from mucinous adenocarcinoma of the gastrointestinal tract or ovary, smooth muscle sarcoma, etc. can undergo calcification, which is manifested by the absence of T1WI and T2WI signals within the tumor foci.
(iv) Angiography
Angiography can show the location, size, number and extent of metastatic tumor foci. Digital subtraction angiography, hepatic artery perfusion angiography and pharmacological angiography are beneficial for the demonstration of liver metastases.
The angiographic presentation of hepatic metastases varies depending on the primary lesion and can be divided into 3 types according to their blood supply.
(1) Vascular-rich type or blood supply-rich type: The angiographic manifestation is similar to that of hepatocellular carcinoma, with obvious thickening of hepatic arteries and a large number of tumor vessels of varying thickness and disorderly arrangement can be seen. Vascular lake-like filling, tumor staining is obvious, and tumor staining is sometimes in the form of thick rings, but hepatic artery-venous fistula and portal vein cancer thrombus are rare.
(2) Isovascular type or moderate blood supply type: the hepatic artery can be thickened, and the tumor vessels are more slender and dense, with disorderly arrangement in the form of a network, and the tumor staining is light, mostly in the form of thin ring or honeycomb.
(3) Lack of vascularity or sparse vascularity: In arteriogram, the hepatic artery vasculature is small, and the branches are dendritic or without obvious tumor vessels and tumor staining, and when the tumor is large, the hepatic artery branches can be seen to be displaced by compression, and the parenchymal phase of the liver can be seen to be filled with round-like defects of varying numbers and sizes. Some of the abdominal arteriograms show hepatic metastases with less blood supply, and the super-selective hepatic arteriograms can show ischemic or multi-blood supply type.
IV. Interventional treatment
The treatment of liver metastases should be combined with the treatment of the primary lesion, and the current treatment methods include surgical treatment and non-surgical treatment, less than 20% of which can be surgically removed. Non-surgical treatment includes radiotherapy, chemotherapy, biological treatment and Chinese medicine treatment, etc. Interventional treatment is an important local treatment method that can accommodate the above-mentioned non-surgical treatments and is the most effective one among the non-surgical treatments, which has the advantages of relatively low systemic toxic side effects, precise local efficacy, minimally invasive and repeatable, etc. It is deeply researched and widely used by both doctors and patients.
(i) Indications and contraindications of interventional therapy
With the improvement of access devices and equipment and the improvement of super-selective intubation techniques, the indications for interventional treatment have been broadened, but the selection of appropriate cases is of great significance to ensure patient safety and successful surgery and good outcomes. Absolute contraindications are rare at the current level of interventional therapy, but some patients should be listed as contraindications because of heavy disease, high risk, high rate of surgical complications or poor treatment effect and prognosis, and patients cannot benefit from interventional therapy or suffer from it instead.
1. Indications for interventional treatment of liver metastases.
(1) Embolization of liver metastases before surgery to reduce intraoperative bleeding and spread or to shrink the tumor for second-stage surgical resection;
(2) Rupture and bleeding of liver metastases;
(3) Palliative treatment of primary tumors that are not curable or undetectable, and liver metastases whether or not combined with extrahepatic metastases;
(4) Although the primary tumor has been resected, but the intrahepatic metastasis is more than one lobe or the compensatory function of the remaining liver is poor, and the intrahepatic tumor is not indicated for surgical resection or the patient is unwilling to receive surgical treatment although hepatic resection is indicated.
2. Contraindications for interventional treatment of liver metastases.
(1) Patients with severe cardiac, pulmonary, hepatic and renal insufficiency, very poor systemic condition, or end-stage patients with obvious cachexia. Severe jaundice;
(2) Severe coagulation mechanism disorder with bleeding tendency or prothrombin time more than 2 times the normal value;
(3) Tumor occupying more than 70% of the liver volume;
(4) Those with extensive systemic metastases;
(5) Severe metabolic diseases (such as diabetes mellitus) that are not controlled;
(6) Combined with serious infections;
(7) Iodine allergy.
(ii) Pre-operative preparation
1. Preoperative examination: Through various preoperative examinations, it is hoped that the following requirements can be met.
(1) Imaging examination to clarify the details of liver metastases;
(2) Clarify the site of the primary tumor foci, pathological type, treatment and efficacy;
(3) To clarify whether there are metastatic tumor foci in other sites besides liver metastases; to clarify whether it is necessary to perform interventional treatment on both the primary foci and metastases in other sites during the interventional treatment of liver metastases;
(4) To clarify whether the patient’s general condition and liver function are suitable for interventional treatment.
(2) Preparation of patients and their families, such as psychological adjustment, understanding of the role of interventional treatment, the process, postoperative reactions, and understanding and cooperation with medical treatment;
3, medical and nursing preparations, such as comprehensive analysis of the patient’s condition, development of detailed interventional treatment plans and implementation measures, preoperative talks with patients and their families and signing informed consent forms, correction of factors unfavorable to interventional treatment, iodine allergy testing, etc;
4. Preparation of drugs and equipment, such as contrast agents, chemotherapeutic drugs, embolic materials, various types of catheter guidewires to be used, allergy prevention drugs, symptomatic drugs such as analgesics, antiemetics, vasodilators, etc.
(iii) Interventional treatment methods and techniques
1. Selective and super-selective cannulation Routine imaging of the celiac artery, hepatic artery, superior mesenteric artery and, if necessary, possible related arteries such as the subphrenic artery. Observe the vascular anatomy and blood perfusion of the hepatic artery. The distribution, morphology, size and number of intrahepatic tumors, blood supply and relationship with intrahepatic vessels are analyzed against CT or MR data. Based on the imaging changes with the vascular anatomy and the proposed treatment, decide whether the intrinsic hepatic artery is to be superselectively cannulated at a distal level with the level of superselective cannulation.
Hyperselective cannulation of the arteries of the liver lobe, segment or subsegment can generally be achieved with a 4-5F preformed catheter with a guidewire. Depending on the tumor site, distribution, number and size, the catheter tip may be located in the intrinsic hepatic artery, the lobar artery or its primary or secondary branches, and in the case of a few small tumor foci it is necessary to superselectively cannulate the regional artery of the tumor. Although the principle requirement is to minimize damage to normal liver tissue, the catheter tip should be located close to the tumor lesion. However, it is usually not possible or necessary to pursue highly selective cannulation for interventional treatment of liver metastases, firstly, because liver metastases are often multiple, scattered, multi-lobe, multi-segment or diffusely involved, and excessive superselection may miss the lesions; secondly, the higher the degree of superselection, the more likely it is to cause vasospasm and produce intolerable pain in patients. Target vasospasm thinning or occlusion obviously affects the treatment of target tumor foci. Fractionated and regional treatment may also be considered for diffuse liver metastases. When treating with hepatic artery perfusion chemotherapy or chemoembolization, care should be taken to minimize the effect of the drug or embolic agent on the gallbladder artery and gastroduodenal artery.
Hepatic arterial chemotherapy (TAI) systemic chemotherapy is not effective for hepatic metastatic cancer. Given that most of the blood of secondary hepatocellular carcinoma also comes from the hepatic artery, while normal hepatocytes are mainly supplied by the portal vein, the chemotherapeutic drugs perfused through the hepatic artery are mostly cleared by the liver due to the first-pass effect, so that the systemic toxicity is greatly reduced when achieving the effect of high local drug concentration in the tumor.
(4) Efficacy evaluation
Interventional therapy is one of the best methods for the efficacy of non-surgical treatment of liver metastases. Its efficacy evaluation can be considered from the following aspects.
①The degree of improvement of the patient’s quality of life.
②The size of tumor and the change of blood supply status; it can be measured by ultrasound, CT, MRI, angiography, etc. It is an important index to judge the efficacy.
③Pathological histological changes: pathological histological changes of tumor after treatment are the most objective index to judge the efficacy. The more complete the necrosis of tumor tissue cells and the less the normal liver tissue is involved, the more successful and effective the treatment is.
(④) Survival rate: The median survival period of liver metastases is 2.5-4.5 months if the natural course of disease is 2-6 months after diagnosis without treatment.
(5) Postoperative treatment After the end of hepatic artery chemoembolization therapy, the hip joint on the puncture side was braked, and the patient was lying flat for 24 hours, given antibiotic rehydration and antiemetic treatment, and the patient’s vital signs changes were closely observed.
Side effects and complications of embolization therapy
Side effects: including nausea, vomiting, abdominal pain, fever and other symptoms, collectively referred to as post-embolization syndrome. The causes are mainly due to tumor tissue necrosis and organ ischemia, edema and vagal reflexes caused by chemoembolization. The treatment measures are symptomatic, malignant, vomiting and abdominal distension can be given with antiemetic drugs, abdominal distension can be given with gastrointestinal dynamics drugs, in clear abdominal pain is acute liver pain caused by tumor ischemia is available morphine intramuscular injection 1-2 times, long-term pain can be used oral extended-release morphine or fentanyl transdermal patch. Postoperative vagal reflex signs such as profuse sweating, slow pulse, and cold extremities should be given oxygen and intramuscular atropine until the pulse becomes faster and the extremities become warm. Dexamethasone 10mg is routinely given intraoperatively via catheter, and 5mg of dexamethasone IV daily for 3 consecutive days after surgery can effectively prevent the absorption fever caused by tumor tissue necrosis after embolization.
(2) Digestive system complications.
① Gastrointestinal tract.
Mucosal lesions: including inflammatory erosions and ulcers of the stomach and duodenum, mostly due to mucosal bleeding caused by the regurgitation of embolic agent into the left gastric artery or the gastric-duodenal artery or direct damage to the gastrointestinal mucosa by chemotherapeutic drugs, and the treatment measures include administration of gastrointestinal mucosal protective agents and anti-acid drugs, etc.
Gastrointestinal bleeding: regurgitation of embolic material into the gastroduodenal artery and direct damage to the mucosa by chemotherapeutic drugs can further lead to upper gastrointestinal bleeding. Preventive measures include intraoperative and postoperative application of gastric mucosal protective agents.
② Biliary tract.
Inflammation: Inflammation can occur in both bile ducts and gallbladder, of which the incidence of cholecystitis is 10% and necrosis occurs in severe cases. Treatment measures include postoperative administration of antispasmodic, anti-inflammatory, and cholestatic therapy.
Perforation: Gallbladder perforation is a serious complication that usually occurs 1-2 weeks after TACE. The cause is embolization of the gallbladder artery caused by the large amount of embolic agent entering the gallbladder artery during hepatic artery embolization, resulting in necrosis of the gallbladder wall. The preventive and curative measures include the catheter tip crossing the gallbladder artery as much as possible when performing hepatic artery embolization; the arteriogram should not be pushed with embolic agent if the gallbladder artery is found to be visualized; if iodinated oil emulsifier is found to enter the gallbladder artery during the pushing of embolic agent, the pushing should be stopped immediately; if medical treatment is ineffective or septic infection of the gallbladder occurs after the diagnosis of gallbladder perforation, surgical operation should be performed.