I. Overview Primary liver cancer (PLC) is a common malignant tumor. Because of insidious onset, no or no obvious symptoms in early stage and rapid progress, most patients have already reached advanced local stage or distant metastasis when diagnosed, which makes treatment difficult and prognosis very poor. Primary liver cancer mainly includes different pathological types such as hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma-intrahepatic cholangiocarcinoma mixed type, which have obvious differences in their pathogenesis, biological behavior, histological morphology, clinical manifestations, treatment methods and prognosis; since HCC accounts for more than 90% of them, what this article refers to “(a) Surveillance and screening of high-risk groups. The etiological factors of liver cancer in China mainly include hepatitis virus infection, food aflatoxin contamination, long-term alcohol abuse and blue-green algae toxin contamination of rural drinking water, other liver metabolic diseases, autoimmune diseases and cryptogenic liver disease or cryptogenic cirrhosis. Since early diagnosis of liver cancer is crucial for effective treatment and long-term survival, early screening and early surveillance of liver cancer are highly emphasized. Routine surveillance screening indicators mainly include serum alpha-fetoprotein (AFP) and liver ultrasonography (US). Screening is generally performed at 6-month intervals for men ≥40 years of age or women ≥50 years of age with HBV and/or HCV infection, alcoholism, comorbid diabetes mellitus, and a family history of liver cancer in high-risk groups. It is generally believed that AFP is a relatively specific tumor marker for HCC, and persistent elevation of AFP is a risk factor for the development of HCC. Recently, some European and American scholars believe that the sensitivity and specificity of AFP is not high, and the 2010 edition of the American Association for the Study of Liver Diseases (AASLD) guidelines no longer use AFP as a screening indicator, but most of the HCC in China is associated with HBV infection, which is different from the causative factors of HCC in western countries (mostly HCV, alcohol and metabolic factors), and combined with the results of domestic randomized studies (RCT) and the actual The situation, the routine monitoring of HCC in the screening indicators continue to retain AFP. (II) Clinical manifestations. 1. Symptoms. Pre-subclinical stage of hepatocellular carcinoma refers to the period from the beginning of the lesion to the diagnosis of subclinical hepatocellular carcinoma, when patients have no clinical symptoms and signs and are difficult to be detected clinically, usually about 10 months. In the subclinical stage (early stage) of hepatocellular carcinoma, the tumor is about 3-5 cm, most patients still have no typical symptoms, so the diagnosis is still difficult, and it is mostly detected by serum AFP census for about 8 months on average, during which a few patients can have symptoms related to chronic underlying liver disease such as epigastric distention, abdominal pain, weakness and loss of appetite. Therefore, for those with high-risk factors, the possibility of hepatocellular carcinoma should be alerted to the occurrence of the above conditions. Once the typical symptoms appear, the disease has often reached the middle or advanced stage of liver cancer, at this time, the disease develops rapidly, about 3-6 months in total, and its main manifestations are: (1) Pain in the liver area. Pain in the right upper abdomen is the most common and is an important symptom of the disease. It is often intermittent or persistent vague, dull or distending pain, which increases with the development of the disease. If the tumor invades the diaphragm, the pain may spread to the right shoulder or the right back; the tumor growing backward to the right may cause pain in the right lumbar region. The cause of pain is mainly due to the tumor growth which makes the liver envelope tense. Sudden onset of severe abdominal pain and peritoneal irritation may be due to peritoneal irritation caused by rupture and bleeding of subhepatic peritoneal cancer nodules. (2) Loss of appetite. Symptoms such as epigastric fullness after meals, indigestion, nausea, vomiting and diarrhea are easy to be ignored because of the lack of specificity. (3) Wasting and weakness. The whole body is weak, and a few advanced patients may present a cachectic condition. (4) Fever. It is more common, mostly persistent low fever, around 37.5-38℃, or irregular or intermittent, persistent or chilling fever, similar to liver abscess, but no chills before fever, and antibiotic treatment is ineffective. The fever is mostly cancer fever, which is related to the absorption of tumor necrotic material; sometimes it can be caused by cholangitis due to the compression or invasion of bile duct by cancer, or fever due to other infections combined with weakened resistance. (5) Symptoms of extrahepatic metastases. For example, lung metastasis can cause cough and hemoptysis; pleural metastasis can cause chest pain and bloody pleural effusion; bone metastasis can cause bone pain or pathological fracture, etc. (6) Jaundice, bleeding tendency (gingival, nasal bleeding and subcutaneous bruises), upper gastrointestinal bleeding, hepatic encephalopathy and hepatic and renal failure are often seen in advanced stage patients. (7) Paraneoplastic syndrome, which is a syndrome of endocrine or metabolic disorders caused by the abnormal metabolism of liver cancer tissue itself or the multiple effects of cancer tissue on the body. The clinical manifestations are diverse and lack of specificity, including spontaneous hypoglycemia, erythrocytosis, hyperlipidemia, hypercalcemia, precocious puberty, gonadotropin secretion syndrome, cutaneous porphyria, abnormal fibrinogenemia and carcinoid syndrome, but they are relatively rare. 2. Physical signs. In the early stage of hepatocellular carcinoma, most patients do not have obvious positive signs, and only a few patients can find mild hepatomegaly, jaundice and skin pruritus on physical examination, which should be non-specific manifestations of the underlying liver disease. In intermediate to advanced hepatocellular carcinoma, jaundice, liver enlargement (hard texture, uneven surface, with or without nodules, vascular murmur) and peritoneal effusion are common. If there is a background of hepatitis and cirrhosis, liver palms, spider nevus, red nevus, abdominal wall varices and splenomegaly can be found. (1) Liver enlargement: It is often progressively enlarged, with hard texture, uneven surface, nodules of different sizes or even giant lumps, with clear margins and often painful to touch and pressure of varying degrees. If the hepatocellular carcinoma protrudes to the right subcostal arch or subxiphoid process, the corresponding area can be seen to be locally full and elevated; if the carcinoma is located on the diaphragmatic surface of the liver, it mainly shows limited elevation of the diaphragm without enlargement of the lower edge of the liver; the carcinoma nodules located on the surface of the liver near the lower edge are most easily palpable. (2) Vascular murmur: Due to the rich and tortuous blood vessels of hepatocellular carcinoma and the sudden thinning of arteries or the compression of hepatic artery and abdominal aorta by cancer mass, about half of the patients can hear wind-like vascular murmur in the corresponding area; this sign has important diagnostic value, but it is not significant for early diagnosis. (3) Jaundice: yellow staining of the skin and sclera, often appearing in the late stage, mostly due to obstruction of the bile duct caused by the cancer or enlarged lymph nodes, or due to hepatocellular damage. (4) Portal hypertension: Patients with hepatocellular carcinoma mostly have a background of cirrhosis, so they often have portal hypertension and splenomegaly. Bloody effusion is mostly caused by cancer breaking into the peritoneal cavity, and can also be caused by peritoneal metastasis; portal vein and hepatic vein cancer embolism can accelerate the growth of peritoneal effusion. 3.Infiltration and metastasis. (1) Intrahepatic metastasis: initially, most hepatocellular carcinoma is intrahepatic metastasis, which easily invades portal vein and its branches and forms tumor embolus, and causes multiple metastases in the liver after shedding. If the stem branch of portal vein is obstructed, it will often cause or aggravate the existing portal hypertension. (2) Extrahepatic metastasis: ①Lung metastasis is the most common, but it can also be metastasized to pleura, adrenal gland, kidney and bone. (2) Lymphatic metastasis, the most common metastasis is from the hilar lymph nodes, but also to the pancreas, spleen and para-aortic lymph nodes, and occasionally to the supraclavicular lymph nodes. Occasionally, the metastasis can be planted in the peritoneum, diaphragm and thorax, causing bloody abdominal and thoracic effusion; in women, ovarian metastasis can occur and form larger masses. 4.Common complications. (1) Upper gastrointestinal bleeding: Hepatocellular carcinoma often has hepatitis and cirrhosis background with portal hypertension, and portal vein and hepatic vein cancer thrombus can further aggravate portal hypertension, so it often causes bleeding from varices of middle and lower esophagus or gastric fundus. If cancer cells invade the bile duct, it may cause biliary bleeding, vomiting blood and black stool. Some patients may bleed extensively due to gastrointestinal mucosa erosion, ulceration and coagulation dysfunction, and heavy bleeding may lead to shock and hepatic coma. (2) Hepatorenal nephropathy and hepatic encephalopathy (hepatic coma): In advanced stage of hepatocellular carcinoma, especially diffuse hepatocellular carcinoma, hepatic insufficiency or even failure can occur, causing hepatorenal syndrome (HRS), i.e. functional acute renal failure (FARF), which mainly manifests as Significant oliguria and decreased blood pressure with hyponatremia, hypokalemia and azotemia, often progressive. Hepatic encephalopathy (HE), i.e. hepatic coma, is often a manifestation of end-stage hepatocellular carcinoma and is often induced by gastrointestinal bleeding, massive diuretics, electrolyte disorders and secondary infections. (3) Rupture and bleeding of hepatocellular carcinoma nodes: It is the most urgent and serious complication of hepatocellular carcinoma. Therefore, gentle palpation is recommended during clinical examination and no forceful pressure should be applied. The rupture of cancer nodules can be confined to the subhepatic peritoneum, causing acute pain and rapid enlargement of the liver, and soft masses can be palpated locally. A small amount of bleeding can be manifested as bloody peritoneal fluid, while a large amount of bleeding can lead to shock or even rapid death. (4) Secondary infection: Patients with hepatocellular carcinoma have weakened resistance due to long-term consumption and bed-rest, especially after chemotherapy or radiotherapy when their white blood cells are reduced, which can easily be complicated by various infections, such as pneumonia, intestinal infection, fungal infection and sepsis, etc. (C) Auxiliary tests. 1. Blood biochemical examination. Hepatocellular carcinoma may show elevation of portal aminotransferase (AST or GOT) and glutamate aminotransferase (ALT or GPT), serum alkaline phosphatase (AKP), lactate dehydrogenase (LDH) or bilirubin, and abnormal liver function such as lower albumin, as well as changes of immune indexes such as lymphocyte subpopulation. Positive hepatitis B surface antigen (HBsAg) or five quantitative tests (including HBsAg, HBeAg, HBeAb and anti-HBc) and/or positive hepatitis C antibodies (anti-HCVIgG, anti-HCVst, anti-HCVns and anti-HCVIgM) are all important signs of hepatitis virus infection. HBV DNA and HCV mRNA can reflect hepatitis viral load. 2. Tumor marker examination. Serum AFP and its heteroplasm is an important indicator and the most specific tumor marker for the diagnosis of hepatocellular carcinoma, and is commonly used for screening, early diagnosis, postoperative monitoring and follow-up of hepatocellular carcinoma in China. For AFP ≥ 400 μg/L for more than 1 month or ≥ 200 μg/L for 2 months, excluding pregnancy, germinal gland embryonal carcinoma and active liver disease, liver cancer should be highly suspected; the key is whether imaging examination (CT/MRI) with characteristic occupancy of liver cancer is performed at the same time. AFP may not be increased in 30%-40% of patients with hepatocellular carcinoma, including those with ICC, highly differentiated and hypofractionated HCC, or HCC with necrosis and liquefaction. Therefore, AFP alone cannot diagnose all hepatocellular carcinoma. The positive rate of AFP for hepatocellular carcinoma diagnosis is generally 60%-70%, and sometimes it varies greatly, emphasizing the need for regular testing and dynamic observation, and the need for imaging or even ultrasound-guided puncture biopsy to clarify the diagnosis. Other markers that can be used to aid in the diagnosis of HCC are various serum enzymes, including r-glutamyl transpeptidase (GGT) and its isoenzymes, alpha-L-arginase (AFU), abnormal prothrombin (DCP), Golgi protein 73 (GP73), 5-nucleotide phosphodiesterase (5’NPD) isoenzyme, aldolase isoenzyme A (ALD-A) and placental glutathione S -transferase (GST), etc., and abnormal prothrombin (DCP), ferritin (FT) and acid ferritin (AIF). In some patients with HCC, there may be abnormal increase of carcinoembryonic antigen (CEA) and glycoantigen CA19-9, etc. 3.Imaging examination. (1) Abdominal ultrasound (US) examination: US examination has become the most common and important method for liver examination because of its easy operation, intuition, non-invasiveness and low cost. This method can determine whether there are occupying lesions in the liver, suggest their nature, identify whether they are fluid or substantial occupations, clarify the specific location of cancer foci in the liver and their relationship with important intrahepatic vessels, so as to guide the selection of treatment methods and surgery; it helps to understand the spread and infiltration of liver cancer in the liver and adjacent tissues and organs. It is of great reference value for the differential diagnosis of hepatocellular carcinoma and liver cysts, hepatic hemangioma and other diseases, but its sensitivity and qualitative accuracy are somewhat affected by the limitations of instrumentation, anatomical site, operator’s technique and experience. Real-time US imaging (ultrasonography CEUS) can dynamically observe the hemodynamic situation of the lesion and help improve the qualitative diagnosis, but it can be false positive for ICC patients and should be noted; while intraoperative US probes directly from the surface of the liver after opening, which can avoid ultrasound attenuation and interference from the abdominal wall and ribs, and can detect small intrahepatic lesions that are not detected by preoperative imaging. (2) Computed tomography (CT): it is the most important imaging method for diagnosis and differential diagnosis of hepatocellular carcinoma, which is used to observe the morphology and blood supply of hepatocellular carcinoma, to detect, characterize and stage hepatocellular carcinoma, and to review hepatocellular carcinoma after treatment; CT has high resolution, especially multi-row spiral CT, which is extremely fast and can scan the whole liver within a few seconds, avoiding breathing motion artifacts; it can perform multi-phase dynamic The minimum layer thickness is 0.5mm, which significantly improves the detection rate and qualitative accuracy of small lesions of liver cancer. Usually, under plain scan, most hepatocellular carcinomas are low-density occupants with different manifestations of clear or blurred edges, some of them have halo signs, and large hepatocellular carcinomas often have central necrosis and liquefaction; it can indicate the nature of lesions and understand whether there are cancer foci in the surrounding tissues and organs of the liver, which can help the localization of radiotherapy; in addition to clearly showing the number, size, morphology and intensification characteristics of lesions, enhanced scan can also clarify the relationship between lesions and important blood vessels, and the relationship between the hilum and the abdomen. The imaging of HCC typically shows significant intensification in the arterial phase, less than that of the surrounding liver tissue in the venous phase, and continuous fading of contrast in the delayed phase, and is therefore highly specific. (3) Magnetic resonance imaging (MRI or MR): no radioactive radiation, high tissue resolution, multi-directional and multi-sequence imaging, superior to CT and US in terms of display and resolution of tissue structural changes inside the hepatocellular carcinoma lesion, such as hemorrhagic necrosis, steatosis and envelope; may be superior to CT in the differentiation of benign and malignant intrahepatic occupancies, especially with hemangioma; meanwhile, it can show the branches of portal vein and hepatic vein without enhancement. MRI is superior to CT for small hepatocellular carcinomas, and there is more evidence. In particular, the increasing popularity and development of high field strength MR equipment has greatly accelerated the speed of MR scanning, which can be completed with thin layer and multi-phase dynamic enhancement scanning like CT, fully displaying the enhancement characteristics of the lesion and improving the detection rate and qualitative accuracy of the lesion. In addition, MR functional imaging techniques (such as diffusion-weighted imaging, perfusion-weighted imaging, and spectral analysis) and the use of hepatocyte-specific contrast agents can provide valuable additional information for lesion detection and characterization, which can further improve the sensitivity and accuracy of hepatocellular carcinoma detection and characterization, as well as the comprehensive and accurate assessment of the efficacy of various local treatments. The above three important imaging techniques have their own characteristics and complementary advantages, and should be emphasized for comprehensive examination and overall assessment. (4) Selective hepatic arteriography (DSA): Currently, digital subtraction angiography is mostly used to clearly show small lesions in the liver and their blood supply, while chemotherapy and iodine oil embolization can be performed. The main manifestations of hepatocellular carcinoma in DSA are: ① tumor vessels, which appear in the early arterial phase; ② tumor staining, which appears in the parenchymal phase; ③ larger tumors can be seen as displacement, straightening and twisting of intrahepatic arteries; ④ intrahepatic arteries invaded by hepatoma can appear as jagged, beaded or stiff; ⑤ arteriovenous fistula; “pool-like” or (5) arteriovenous fistula; “pool” or “lake” contrast-filled area, etc. The significance of DSA examination not only lies in the diagnosis and differential diagnosis, but also can be used to estimate the extent of lesions before surgery or treatment, especially to understand the situation of disseminated sub-nodules in the liver; it can also provide correct and objective information on vascular anatomical variants and anatomical relationships of important vessels as well as portal vein infiltration, which is of great value in judging the possibility and completeness of surgical resection and deciding on a reasonable treatment plan. DSA is an invasive DSA is an invasive test and can be used for patients whose diagnosis cannot be confirmed after other tests. In addition, for resectable hepatocellular carcinoma, even if the imaging shows limited resectable hepatocellular carcinoma, some scholars advocate preoperative DSA, which has the potential to detect lesions that cannot be detected by other imaging means and clarify the presence of vascular invasion. (5) Positron emission computed tomography (PET-CT): PET-CT is a functional molecular imaging system integrating PET and CT, which can reflect the biochemical and metabolic information of liver occupancy by PET functional imaging, and precisely locate the lesion by CT morphological imaging, and the whole-body scan can understand the overall condition and evaluate the metastasis to achieve early detection of the lesion. The purpose of early detection of lesions can be achieved, and the size and metabolic changes before and after tumor treatment can be understood. However, the sensitivity and specificity of PET-CT for clinical diagnosis of liver cancer need to be further improved, and it has not yet been popularly used in most hospitals in China, so it is not recommended as a routine examination for liver cancer diagnosis, but can be used as a supplement to other means. (6) Emission single photon computed tomography (ECT): ECT whole-body bone imaging is helpful for the diagnosis of bone metastasis of liver cancer, and can detect bone metastasis 3-6 months earlier than X-ray and CT examination. 4.Liver aspiration biopsy . Core biopsy or fine needle aspiration (FNA) can be performed under ultrasound guidance for histological or cytological examination to obtain pathological diagnosis of hepatocellular carcinoma and molecular markers, which are very important for definite diagnosis, pathological type, judgment of disease, guidance of treatment and prognosis assessment. It is very important for definite diagnosis, pathological type, judgment, treatment and prognosis, and has been increasingly used in recent years, but it also has certain limitations and risks. When performing liver aspiration biopsy, care should be taken to prevent liver bleeding and needle tract cancer cell implantation; contraindications are patients with significant bleeding tendency, severe cardiopulmonary, cerebral and renal disorders and systemic failure.