Primary liver cancer is a highly malignant cancer with strong infiltration and metastasis, and surgery is the first choice for treatment. However, most patients are already in the middle or late stage when they are diagnosed and can only receive non-surgical treatments such as intervention, ablation, radiotherapy and chemotherapy. The emergence of molecular-targeted drugs represented by sorafenib has provided a new choice for such patients. At present, there is still a lack of standardized guidance on the diagnosis and treatment of liver cancer in China, and the Expert Consensus on Standardized Diagnosis and Treatment of Primary Liver Cancer, which is written by multidisciplinary experts from all over the country, has come into being. 1 . Preface Primary liver cancer (PLC, hereinafter referred to as hepatocellular carcinoma) is one of the most common malignant tumors in clinical practice, and the global incidence rate is increasing year by year, which has exceeded 626,000/year, ranking 5th among malignant tumors; the deaths are close to 600,000/year, ranking 3rd among tumor-related deaths. Hepatocellular carcinoma is highly prevalent in our country, and at present, the number of incidence in our country accounts for about 55% of the world; it ranks second only to lung cancer in tumor-related deaths. Therefore, liver cancer is a serious threat to the health and life of our people. In order to promote the development of clinical oncology in China, improve the multidisciplinary standardized comprehensive treatment and research level of hepatocellular carcinoma, actively learn and apply domestic and foreign high-level evidence in line with the principles of evidence-based medicine, and formulate clinical practice guidelines for hepatocellular carcinoma in line with the national conditions of our country, the Hepatology Committee of the Chinese Society of Liver Cancer (CSLC), the Collaborative Committee of Clinical Oncology of the Chinese Society of Liver Cancer (CSCO), and the Hepatology Branch of the Chinese Medical Association (CMC) have developed a series of clinical guidelines for liver cancer. The Liver Cancer Group of the Chinese Medical Association Branch of Hepatology co-sponsored and organized the participation of multidisciplinary experts to formulate this Expert Consensus on Standardized Diagnosis and Treatment of Primary Liver Cancer. On November 10, 2007, April 5 and August 30, 2008, three expert consensus seminars were held in Shanghai. The meetings were co-chaired by Prof. Ye Shenglong and Prof. Qin Shukui, under the guidance of Academician Wu Mengchao, Academician Tang Zhaoyou, Academician Sun Yan and Prof. Guan Zhongzhen, and attended by more than 60 famous experts in the field of hepatocellular carcinoma diagnosis and treatment in China. During the meeting, experts systematically reviewed the current international guidelines and consensus on liver cancer, and discussed a series of issues such as diagnosis of liver cancer, surgical treatment (hepatic resection and liver transplantation), interventional therapy, local ablation therapy (mainly including radiofrequency ablation, microwave ablation and high-intensity focused ultrasound therapy), radiotherapy, biotherapy, molecular targeted therapy, systemic chemotherapy and traditional Chinese medicine treatment. The experts prepared seriously and actively participated in the meeting. Based on the principle of respecting the evidence of evidence-based medicine and aligning with the international diagnosis and treatment concepts, especially for the current situation and development of the diagnosis and treatment of hepatocellular carcinoma in China, they expressed their views and pooled their ideas, and put forward a lot of good suggestions. After the meeting, some experts wrote and widely solicited opinions, and finally formed the Expert Consensus on Standardized Diagnosis and Treatment of Primary Liver Cancer, which was revised many times. 2. Evaluation of International Hepatocellular Carcinoma Treatment Guidelines and Consensus Since most of the liver cancers are hepatocellular carcinoma (HCC), the clinical management of which involves many disciplines, such as internal medicine, surgery, interventional therapy, radiotherapy, traditional Chinese medicine, and medical imaging, it is necessary for multidisciplinary experts to discuss and formulate the standardized diagnosis and treatment of hepatocellular carcinoma in order to select the most suitable preferred treatment and comprehensive treatment measures for the patients after the diagnosis. At present, there are international guidelines for liver cancer treatment for reference, mainly including: (1) National Comprehensive Cancer Network (NCCN) clinical practice guidelines for liver cancer; (2) American Association for the Study of Liver Diseases (AASLD) clinical treatment guidelines for HCC; (3) British Society of Gastroenterology (BSG) treatment guidelines; (4) Consensus formulated by the American College of Surgeons (ACS). Staging of hepatocellular carcinoma The staging of HCC is not uniform in the guidelines of AASLD, ACS and NCCN, and the emphasis is different. The TNM staging method adopted by NCCN is the most standardized internationally, but is less recognized because: (1) vascular invasion, which is crucial to the treatment and prognosis of HCC, is difficult to be accurately determined before treatment (especially before surgery); (2) the treatment of HCC puts great emphasis on hepatic function compensation, and the TNM staging does not indicate the status of the patient’s hepatic function; (3) there are large variations in the various versions of TNM staging, which makes it difficult to compare and evaluate. (iii) TNM staging varies greatly from one version to another, making it difficult to compare and evaluate. AASLD adopts the Barcelona Clinical Liver Cancer (BCLC) staging and treatment strategy, which more comprehensively considers the tumor, liver function and systemic conditions, and is supported by high-level evidence of evidence-based medicine, and is now more recognized and widely adopted worldwide. Surveillance and screening of hepatocellular carcinoma The four international guidelines mentioned above all place great emphasis on early screening and early surveillance of hepatocellular carcinoma, which are all based on evidence-based medicine and have a high degree of credibility. There is a relatively consistent view on screening indicators, which mainly include two items: serum alpha-fetoprotein (AFP) and liver ultrasonography. For men ≥35 years of age, those at high risk of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, and alcoholism, screening is generally performed at 6-month intervals. For those with AFP >400 μg/L and no liver occupancy detected by ultrasound, care should be taken to exclude pregnancy, active liver disease, and tumors of embryonic origin in the gonads; if this can be excluded, CT and/or magnetic resonance imaging (MRI) should be performed. If AFP appears to be elevated but does not reach the diagnostic level, in addition to the above conditions that may cause AFP increase should be excluded, the dynamic change of AFP should be closely tracked, the interval of ultrasonography should be shortened to one to two months, and CT and/or MRI should be performed when needed. If hepatocellular carcinoma is highly suspected, digital subtraction angiography (DSA) hepatic artery iodine-oil angiography is recommended. Diagnosis of hepatocellular carcinoma The diagnostic criteria for HCC include pathologic diagnostic criteria and clinical diagnostic criteria. Diagnostic methods include serum tumor marker AFP test, imaging examinations (including ultrasound, CT, MRI, and DSA, etc.), and pathological histological examinations (mainly liver tissue biopsy). The BSG guidelines suggest that for patients with cirrhosis, the presence of cirrhosis should first be determined, and subsequently the diagnostic process should begin with a limit of 2 cm for the size of the occupying space; whereas for non-cirrhotic patients, the AFP level is used to guide the diagnostic process. Internationally, the diagnostic process of AASLD is currently applied more often, with the occupancy of <1 cm, 1-2 cm and >2 cm, to differentiate the mass and the diagnostic process, with emphasis on early diagnosis. Treatment of hepatocellular carcinoma The consensus of ACS states that the goals of treatment for HCC include: ① cure, ② local control of the tumor in preparation for transplantation, and ③ local control of the tumor and palliative care. Improving the quality of life is also one of the important treatment goals. Treatments broadly include surgical treatments (hepatectomy, liver transplantation, and palliative care surgery), non-surgical treatments (local therapy, arterial chemoembolization, chemotherapy, radiotherapy, biologic therapy, and molecularly-targeted therapy), and other therapeutic approaches (including participation in clinical studies). The NCCN emphasizes keeping abreast of the times while following evidence-based medicine, and its 2008 edition of treatment guidelines has introduced breakthroughs in the field of liver cancer treatment in the past two years, namely listing the molecular targeted therapy drug sorafenib as one of the standard treatment choices for patients with inoperable and advanced HCC. 3. Diagnosis of primary liver cancer Early diagnosis of liver cancer Early diagnosis of liver cancer Early diagnosis of primary liver cancer (PLC, hereinafter referred to as liver cancer) is crucial. Since the 1970s to 1980s, the early diagnosis of liver cancer has been greatly facilitated by the gradual popularization and wide application of serum alpha-fetoprotein (AFP), real-time ultrasonography and CT. Since the early diagnosis rate has been significantly increased, the surgical resection rate has been increased, and the prognosis has been significantly improved, the diagnosis of liver cancer, especially the early diagnosis, is the key to clinical diagnosis and prognosis. In terms of early diagnosis, the background of liver disease of patients should be fully emphasized. In China, 95% of liver cancer patients have the background of hepatitis B virus (HBV) infection, 10% have the background of hepatitis C virus (HCV) infection, and some patients have the overlapping infection of HBV and HCV. Special attention should be paid to the following risk groups: middle-aged and elderly men with high HBV loads, HCV-infected patients, patients with overlapping HBV and HCV infections, alcoholics, patients with diabetes, and patients with a family history of liver cancer. After the age of 35 to 40, these people should undergo regular screening (including serum AFP test and liver ultrasound) every 6 months; when there is elevated AFP or “occupying lesions” in the liver area, they should enter the diagnostic process immediately, and closely observe the situation in order to make early diagnosis. Laboratory diagnostic methods of hepatocellular carcinoma At present, the qualitative diagnosis of hepatocellular carcinoma in China is still based on the detection of serum AFP, which should be attached great importance to: 1) In China, more than 60% of hepatocellular carcinoma cases have serum AFP >400 μg/L; 2) At present, there is no other tumor marker whose specificity can be compared with that of AFP; 3) The detection of AFP less relies on the imaging equipments and new technologies. Imaging diagnostic methods for liver cancer In recent years, the progress of medical imaging means is obvious, which provides a reliable basis for the “four definitions” (localization, qualification, quantification, and periodicity) and the formulation of treatment plans for liver cancer. Ultrasonography Ultrasonography is non-invasive and has no adverse effect on human tissues. It is simple in operation, intuitive and accurate, inexpensive, convenient, non-invasive and widely popularized, and can be used in the census of hepatocellular carcinoma and follow-up after treatment. Real-time ultrasonography has important clinical value for the differential diagnosis of small hepatocellular carcinoma and is often used for the early detection and diagnosis of hepatocellular carcinoma, and is more informative for the differential diagnosis of hepatocellular carcinoma from hepatic cysts and hepatic hemangiomas. Intraoperative ultrasonography directly probes the surface of the liver after laparotomy, which avoids ultrasonographic attenuation and the interference of the abdominal wall and ribs, and can detect small intrahepatic lesions that are not detected by preoperative CT and ultrasonography. However, ultrasonography is easily affected by the experience, technique and meticulousness of the examiner. Multi-slice CT CT has a much higher resolution than ultrasound, with clear and stable images, which can reflect the characteristics of liver cancer comprehensively and objectively, and is used for routine diagnosis of liver cancer and follow-up examination after treatment. CT has the following advantages: CT enhancement scan can clearly show the size, number, shape, location, boundary, richness of blood supply of the tumor and its relationship with intrahepatic ducts; it has important diagnostic value for whether there are cancer embolisms in portal, hepatic vein and inferior vena cava, metastasis of hepatic hilar and abdominal lymph nodes, and whether the liver cancer invades the neighboring tissues and organs; and it can show the shape of liver, size of spleen, and whether there is ascites to determine whether there is liver cancer. It can also determine the severity of cirrhosis by showing the shape of liver, the size of spleen and the presence or absence of ascites, therefore, CT has become an important routine means of diagnosis of hepatocellular carcinoma. In particular, CT dynamic enhancement scan can significantly improve the detection rate of small liver cancer; CT scan after 3-4 weeks of hepatic artery iodine oil embolization can also effectively detect small liver cancer lesions. Magnetic resonance imaging (MRI) MRI has the characteristics of high tissue resolution, multi-parameter and multi-directional imaging, and no radiation effect, so MRI is another efficient and non-invasive liver cancer examination and diagnosis method after CT. The application of liver-specific MRI contrast agent can improve the detection rate of small hepatocellular carcinomas, and it is also helpful in differentiating hepatocellular carcinomas from focal hyperplastic nodules and hepatic adenomas, etc. In addition, for the tracking and observation of the therapeutic efficacy of hepatic arterial chemoembolization (TACE) in patients with hepatocellular carcinomas, MRI is of higher clinical value than CT, and it has unique features in the detection of small intra-hepatic foci, the vascular condition, as well as the structure of tumors and their necrotic condition. MRI has unique features and can be an important supplement to CT examination. PET-CT PET-CT is a functional molecular imaging system that integrates PET and CT, which can reflect the biochemical and metabolic information of liver occupancy by PET functional imaging, and carry out precise anatomical localization of lesions by CT morphology imaging, and at the same time, whole-body scanning can be used to understand the overall condition and assess the metastatic situation, so as to achieve the purpose of early detection of lesions, and at the same time, it can understand the treatment of tumor. At the same time, the whole body scan can understand the overall condition and assess the metastatic situation, so as to achieve early detection of lesions, and at the same time, understand the size and metabolic changes of the tumor before and after treatment. Selective hepatic arteriography Selective hepatic arteriography is an invasive examination, while chemotherapy and iodine oil embolization also have therapeutic effect, which can clearly show the small lesions in liver and their blood supply, and selective hepatic arteriography is suitable for the patients who can not be diagnosed after other examinations. Hepatocellular carcinoma ” five large and six subtypes”: 1) diffuse type, small cancer nodules are diffusely distributed in the whole liver; 2) massive type, the diameter of tumor is more than 10 cm; 3) lumpy type, the diameter of tumor is between 5 and 10 cm, according to the number of lumps and their morphology, it is divided into single-lump, fused-lump, and multi-mump; 4) nodular type, the diameter of tumor is between 3 and 5 cm, according to the number of nodules and morphology, it is divided into single lump, fused lump, and multi-mump; 4) nodule type, the diameter of tumor is between 3 and 5 cm. 4. Nodular type: the diameter of the tumor is between 3 and 5 cm, and according to the number and morphology of the nodules, it can be divided into single-nodule type, fusion nodule type and multi-nodule type; 5. Small cancer type: the diameter of the tumor is less than 3 cm. Edmondson-Steiner grading method: Grade Ⅰ: the cancer cells are in a highly differentiated state, with a nuclear/plasmic ratio close to normal; Grade Ⅱ: the cancer cells are in a moderately differentiated state but with an increase in the nuclear/plasmic ratio and a deeper nuclear staining; Grade Ⅲ: the cancer cells are poorly differentiated, and the nuclear/plasmic ratio is even darker. Grade III: cancer cells are poorly differentiated, with higher nuclear/protoplasmic ratio, obvious nuclear heterogeneity, and many nuclear divisions; Grade IV: cancer cells are the most poorly differentiated, with little cytoplasm, thickly stained nuclear chromatin, and extremely irregular and loosely arranged cell shape. Pathologic diagnosis of hepatocellular carcinoma Pathologic examination is the gold standard for diagnosing primary hepatocellular carcinoma, but special attention should be paid to combining with clinical examination. Pathologic histology of hepatocellular carcinoma is mainly divided into three types: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and mixed hepatocellular carcinoma. Fibrous platysmal carcinoma is a special type of HCC, which is commonly seen in adolescents, mostly without cirrhosis, with slow growth and better prognosis. In view of the differences between HCC and ICC in terms of pathogenesis, biological characteristics, clinical manifestations, treatment methods and prognosis, attention should be paid to the differentiation, and corresponding diagnostic and therapeutic specifications should be formulated respectively. The main diagnostic bases are as follows: 1. HCC is most commonly found in a trabecular arrangement, with polygonal cancer cells, eosinophilic cytoplasm, round nuclei, and blood sinusoids lining the trabeculae; however, a variety of cytological and histological special types, such as common pseudo-glandular duct structures, can also be present, which require careful differential diagnosis. Representative immunohistochemical staining: Hepatocyte antigen (Hep Par1) shows cytoplasmic positivity, polyclonal carcinoembryonic antigen (pCEA) shows cell membrane (capillary bile ducts) positivity, and CD34 shows diffuse positivity of microvessels. 2.General typing of HCC can refer to the classification of “five major types and six subtypes” formulated by the Chinese Collaborative Group for Pathological Research of Liver Cancer in 1979, and the degree of differentiation of cancer cells can refer to the Edmondson-Steiner four-grade grading method. 3. ICC is predominantly glandular-tubular arrangement, with cuboidal or low columnar cancer cells, pale or basophilic cytoplasm, and abundant fibrous interstitium. However, a variety of cytological and histological special types can occur, which need to be carefully differentiated and diagnosed. Representative immunohistochemical stains: cytokeratin 19 (CK19) and mucin-1 (MUC-1) show positive cytoplasm. 4.The general types of ICC can be classified as nodular, periductal infiltrating and nodal infiltrating, and the degree of differentiation of cancer cells can be classified as good, medium and poor. Mixed hepatocellular carcinoma is the presence of both hepatocellular carcinoma and cholangiocarcinoma in a single hepatocellular carcinoma nodule, and the biological characteristics are between the two types. Small hepatocellular carcinoma is not exactly equivalent to the concept of early hepatocellular carcinoma. Some small hepatocellular carcinomas may have tiny metastases at early stage, and their surgical resection may not be very effective; in addition, early hepatocellular carcinoma does not completely mean that the liver function is in a state of compensation, and it does not mean that all of them are resectable. The contents of pathological diagnosis report should include: tumor site, size, number, cell and histological type, differentiation degree, vascular and peripheral invasion, satellite foci and metastatic foci, as well as hepatic tissue lesions next to the cancer, etc. The report can also be accompanied with the information of the liver cancer, which is related to the liver cancer. The report can also be accompanied by the results of immunohistochemistry and molecular markers related to drug targeting molecules, biological behavior and prognosis of liver cancer for clinical reference. 4. Surgical treatment of primary liver cancer The surgical treatment of primary liver cancer (PLC, hereinafter referred to as liver cancer) includes hepatectomy and liver transplantation. The basic principles of hepatectomy include: (1) thoroughness: complete resection of the tumor with no residual tumor at the margin; (2) safety: preservation of normal liver tissues as much as possible to reduce the incidence of surgical mortality and surgical complications. Liver functional reserve should be evaluated before surgery, usually using Child-Pugh classification to evaluate liver parenchymal function and CT and/or magnetic resonance imaging (MRI) to calculate the remaining liver volume. Classification of methods of hepatic resection Methods of hepatic resection include radical and palliative resection. Radical resection refers to: (1) the number of tumors is not more than 2; (2) there is no thrombus of portal vein trunk and its first level branches, common hepatic duct and its first level branches, hepatic vein trunk and inferior vena cava; (3) there is no intra- or extra-hepatic metastasis, and the tumors are completely resected to the naked eye, with no residual cancer at the margins of the incision; (4) there is no residual tumor in the postoperative imaging examination, and the serum AFP of those who have a positive alpha-fetoprotein (AFP) before the operation is reduced to normal within two months of the postoperative follow up. Indications for surgical treatment of hepatocellular carcinoma With the advancement of modern liver surgical techniques, tumor size is not a key limiting factor for surgery. Whether resection can be performed and the efficacy of resection are not only related to the size and number of tumors, but also have a very close relationship with liver function, degree of cirrhosis, tumor location, tumor boundaries, presence or absence of intact peritoneum and venous cancer thrombus. Indications for liver cancer surgery issued by the Hepatology Group of Chinese Surgical Association General condition of patients (essential conditions): good general condition, no obvious organic lesions of heart, lung, kidney and other important organs; normal liver function, or only mild damage (Child-Pugh class A), or liver function grade B, recovered to class A after short-term hepatoprotective treatment; hepatic reserve function [e.g., indocyanine green 15-minute retention rate (ICGR15)] is essentially within the normal range; and there is no non-resectable extrahepatic metastatic tumor. Localized lesions for radical hepatectomy should meet the following conditions: (1) single hepatocellular carcinoma with smooth surface, clear peripheral boundaries or pseudo-coated membrane, with <30% of liver tissue destroyed by the tumor, or >30% of liver tissue destroyed by the tumor, but with compensatory enlargement of the non-tumor-bearing side of the liver to more than 50% of the total liver tissue; (2) multiple tumors, with <3 nodules, confined to a segment or a lobe of the liver. Palliative hepatectomy is feasible for localized lesions subject to the following conditions: ① 3 to 5 multiple tumors, beyond the scope of half of the liver, multiple limited resection; ② tumor is confined to the adjacent 2 to 3 liver segments or half of the liver, the tumor-free liver tissue obviously compensatory enlargement of the liver more than 50% of the liver; ③ hepatocellular carcinoma of the central region of the liver (middle lobe or segments Ⅳ, Ⅴ, Ⅷ), the tumor-free liver tissue obviously compensatory increase in liver tissue up to the liver more than 50%; ④ lymphatic in the hilar region, the liver is obviously compensated for the liver tissue. For those with lymph node metastasis in the porta hepatis, lymph node dissection or postoperative treatment should be carried out at the same time of tumor resection; ⑤ For those with invasion of peripheral organs, resection should be carried out together. Palliative hepatic resection also involves the following cases: hepatic cancer combined with portal vein thrombosis (PVTT) and/or vena cava thrombosis, hepatic cancer combined with bile duct thrombosis, hepatic cancer combined with cirrhosis and portal hypertension, and resection of difficult to resect hepatocellular carcinoma. Each case has its corresponding indication for surgical treatment (Table 1). In addition, for hepatocellular carcinoma that is not suitable for palliative resection, palliative non-resectable surgical treatments, such as intraoperative hepatic artery ligation and/or hepatic artery and portal vein cannulation for chemotherapy, should be considered. The treatment of microscopic intrahepatic lesions deserves attention. Some of the microscopic lesions cannot be detected by imaging or intraoperative exploration, resulting in an increased recurrence rate after hepatic resection. If incomplete resection is suspected, postoperative hepatic artery chemoembolization (TACE) is ideal, because it has the significance of detecting residual cancer foci in addition to treatment. If there are residual cancer foci, timely remedial measures should be taken. In addition, hepatitis viral load [Hepatitis B virus (HBV) DNA/Hepatitis C virus (HCV) RNA] test should be performed in postoperative cases, and antiviral treatment should be performed if indicated to minimize the possibility of recurrence of hepatocellular carcinoma.