Primary liver cancer (hereafter referred to as liver cancer) is one of the common malignant tumors and the third most common malignant tumor in China, with the incidence rate increasing year by year. In recent decades, the clinical diagnosis and treatment techniques of liver cancer have developed rapidly. The use of various modern imaging techniques, the improvement of surgical techniques, the advancement of non-surgical local treatment and the perfection of perioperative treatment, the development of liver transplantation for early-stage liver cancer and the development of traditional Chinese medicine treatment have significantly improved the recent efficacy of liver cancer after surgery. However, the high recurrence rate after surgery seriously affects the long-term efficacy of surgery. Therefore, it has become an important clinical research topic to further understand the factors related to recurrence and metastasis of hepatocellular carcinoma, discover new and more specific indicators for early diagnosis of recurrence and metastasis, and provide appropriate treatment for recurrence and metastasis to improve the long-term outcome of hepatocellular carcinoma.1. Incidence of recurrence and metastasis after radical surgical resection of hepatocellular carcinoma and related factors Recurrence of hepatocellular carcinoma is divided into intrahepatic recurrence and extrahepatic metastasis. The former is divided into single, multiple or diffuse intrahepatic spread; the latter refers to the distant spread of the primary lesion of hepatocellular carcinoma, which can be both intrahepatic recurrence and distant metastasis at the same time. Recent recurrence (within 3a) is mostly dissemination of primary foci, while advanced stage is mostly multicentric hepatocellular carcinoma with better prognosis than the former. The literature reports that the recurrence rate is the highest within 2a after surgery, which is 62%-82%. Therefore, 2a after surgery is the “high risk period for recurrence of hepatocellular carcinoma”. The site of recurrence and metastasis of hepatocellular carcinoma is 90% in the liver and 10% in the lung. It can also occur in bones, chest, abdomen, soft tissues, brain and mediastinum. About 10% of the cases have 2 simultaneous recurrences (1). Three cases of skin implantation at the incision and drainage tube after resection of hepatocellular carcinoma have been reported (2). The recurrence rate of 5a after radical resection for hepatocellular carcinoma was 61.5% in 1650 cases and 43.5% in small hepatocellular carcinoma (<5 cm) according to the Institute of Liver Cancer, Shanghai Medical University. Risk factors include: high r-GT, symptomatic patients with large nodular cirrhosis, and portal vein thrombosis (3). Wu Mengchao et al. reported a recurrence rate of 72.3% at 5a after radical resection for hepatocellular carcinoma and 35.4% for small hepatocellular carcinoma in 1243 cases (4). The main reasons for recurrence of hepatocellular carcinoma after radical resection are as follows: 1) incomplete resection of hepatocellular carcinoma and continued growth of residual carcinoma after surgery; 2) preoperative invasion of hepatic vein or portal vein by hepatocellular carcinoma to form cancer thrombus or the existence of early metastases in the liver; 3) multicentric occurrence of primary hepatocellular carcinoma; 4) de novo hepatocellular carcinoma foci, some patients may have the possibility of generating new carcinoma foci due to some carcinogenic mechanism, which can hardly be avoided even after radical resection. Lise summarized the follow-up data of 100 patients with hepatectomized liver cancer, and the 5a recurrence rate was 56.2%, 5a survival rate was 38%, and 5a tumor-free survival (DFS) rate was 26%. The independent factors associated with tumor-free survival were: Child classification (all Child B grade recurrence), liver function index, AFP concentration, number of intrahepatic tumor nodes, extent of surgical resection, preoperative chemotherapeutic drug embolization therapy, and surgical technique and experience, respectively. Independent factors associated with survival were Child classification and extent of surgical resection. It was concluded that patients with hepatocellular carcinoma with normal liver function had a long postoperative tumor-free survival. Recurrence is bound to occur in patients with hepatocellular carcinoma with poor liver function or inadequate extent of resection. Although preoperative chemo-drug embolization therapy significantly prolongs tumor-free survival, it can also increase the risk of postoperative liver failure in patients with poor liver function (5). It is worth mentioning that the biological characteristics of hepatocellular carcinoma remain the most important factor affecting the prognosis of hepatocellular carcinoma (mainly recurrence): among them, patients with multiple tumors, those without an envelope, those with cancer thrombi, hepatocellular carcinoma with heteroploidy, and those with high expression of proliferating cell nuclear antigens have a poorer prognosis (8). Another important factor is the multicentric occurrence of hepatocellular carcinoma. In recent years, HBV-DNA integration and P53 genotype were used to study the origin of recurrence of hepatocellular carcinoma, and it was confirmed that recurrence occurs both unicentrically and multicentrically, and distant recurrence is often multicentric (9).2. Early detection of recurrence and metastasis of hepatocellular carcinoma is an important aspect for the early detection of recurrence in the subclinical stage, and regular and long-term postoperative follow-up. For patients with AFP-positive hepatocellular carcinoma, postoperative monitoring of AFP and ultrasound localization diagnosis can detect recurrent lesions in a more timely manner. It should be noted that the negative rate of AFP detection in primary liver cancer is as high as 30%~40%, and the level of AFP detection before treatment cannot predict the risk of recurrence and metastasis after hepatectomy. If we can rely on one or several biological indicators to screen out the high-risk candidates for recurrence and metastasis before treatment, it will be beneficial for formulating clinical individualized treatment plans and guiding follow-up. In recent years, with the continuous research on the mechanism of recurrence and metastasis after hepatocellular carcinoma resection, some indicators related to the recurrence of metastasis after hepatocellular carcinoma surgery have been discovered. ① Telomerase activity: ohta reported that the positive rate of telomerase activity in 29 cases of hepatocellular carcinoma cancer tissues was 95.8%. The positive rate of telomerase activity in surgically resected paracancerous liver tissues was 36.8%, among which 71% of patients showed recurrence six months after surgery. Therefore, telomerase activity in paracancerous liver tissue can be one of the useful indicators to predict postoperative recurrence (10). 20 patients with liver resection for hepatocellular carcinoma were followed up by Sinda, and the quantitative value of telomerase activity in 9 patients with early intrahepatic recurrence was 36.4+/-27.8, which was much higher than that in 11 patients without recurrence, which was 9.84+/-7.65. This indicates that the quantitative telomerase activity value can be used as an indicator to monitor liver cancer early recurrence of metastasis (12). ②Inflammatory cell infiltration: Wada investigated the relationship between primary hepatocellular carcinoma with inflammatory cell infiltration and prognosis from a clinicopathological perspective. The experimental group consisted of 11 cases of HBsAg(-) , HCvAb(+) primary hepatocellular carcinoma with significant inflammatory cell infiltration; the control group consisted of 152 cases of HBsAg(-) , HCvAb(+) primary hepatocellular carcinoma without inflammatory cell infiltration; as a control group, a group of 116 primary hepatocellular carcinoma patients with HCvAg(+) alone. 5a recurrence rates were 9.1%, 47.7%, and 47.5 %, respectively. The 5a recurrence rates were 9.1%, 47.7%, 47.5%, 5a survival rates were 100%, 65.1% and 68.1%, combined with cirrhosis were 54.5%, 77.0% and 78.4%, and invasion of portal vein were 9.1%, 35.5% and 29.3%, respectively. It was concluded that primary hepatocellular carcinoma with inflammatory cell infiltration has a better prognosis (12). The average tumor-free survival of patients with high Cyclin A expression was 6 months, while the average tumor-free survival of patients without high Cyclin A expression was 29 months. This suggests that high Cyclin A expression is an independent prognostic factor relative to tumor recurrence (13). ④ Loss of chromosomal heterozygosity (LOH): Nakamori followed 54 patients undergoing hepatectomy for 3a and selected 13 microsatellite loci corresponding to six chromosome arms 1p, 4q, 8p, 16q and 17p for analysis and found that patients with hepatocellular carcinoma with loss of 13q heterozygosity all had a shorter tumor-free survival. Low DFS was significantly associated with tumor growth invasion and pathological TNM stage, but not with other aspects such as cirrhosis, hepatitis virus infection, high level of AFP, or histological type. 13q heterozygosity loss can be used as an indicator to monitor early tumor recurrence after hepatocellular carcinoma surgery and provide more correct information for postoperative follow-up in high-risk subjects (14). ⑤ AFP mRNA in circulating blood: AFP mRNA in circulating blood can be a useful indicator to detect the presence of cancer cells in circulating blood, and the positive rate of AFP mRNA in peripheral blood [of patients with hepatocellular carcinoma] was 53.8% using RT-PCR. Therefore, it is possible to detect the presence of disseminated liver cancer cells in the blood circulation, i.e. micro-metastases, before deciding on a treatment plan. The positive rate of AFP mRNA in peripheral blood was significantly correlated with the clinical stage and recurrence of hepatocellular carcinoma after surgery, and the expression of AFP mRNA in peripheral blood of hepatocellular carcinoma patients with recurrence after surgery could reach 100%. Therefore, the expression of peripheral blood AFP mRNA can be used as a biological indicator to determine the risk of recurrence and metastasis (15). (7) Expression of matrix metalloproteinase-9 (MMP-9): In the process of tumor invasion and metastasis, tumor cells have to break through the extracellular matrix and basement membrane barriers, and MMP-9 can degrade the extracellular matrix, so those with high MMP expression have a higher invasion and metastasis ability. Studies have shown that most patients with high MMP-9 expression in liver cancer tissues and high plasma MMP-9 levels have portal vein cancer thrombosis or intrahepatic metastasis (16-17). (8) Vascular endothelial growth factor (VEGF):VEGF is considered to be one of the most potent and specific vascular growth factors found so far, and high expression of VEGF is closely related to recurrence and metastasis of liver cancer. The study showed that the positive rate of VEGF expression in recurrent and metastatic group was 86.2%, which was significantly higher than that in non-metastatic recurrent group (18).3. Treatment of recurrent metastasis of primary liver cancer 3.1 Re-surgical resection is the preferred treatment for recurrence of liver cancer Recurrence after radical resection of primary liver cancer is very common, and there is no uniform standard for treatment. Traditionally, it is believed that once recurrence of hepatocellular carcinoma occurs after surgery, it is an advanced case and should not be operated again. However, clinical practice shows that if appropriate examination and treatment measures are taken according to the site, size and systemic condition of recurrence in a planned and systematic manner, it is possible to achieve more satisfactory results. Cancer recurrence is the main cause of late death after hepatectomy. The recurrence rate of large hepatocellular carcinoma is 80% after radical resection in 5a, and small hepatocellular carcinoma can reach 40%--50%. More than 90% of them are intrahepatic recurrences (1). Reoperative resection is the preferred treatment for hepatocellular carcinoma recurrence. Wu Mengchao reported that 123 patients with recurrent intrahepatic cancer were treated by re-excision; the survival rates were 83.5%, 38.2%, and 19.6% for 1, 3, and 5a after secondary surgery, and 94.7%, 44.9%, and 25.0% for 1, 3, and 5a after tertiary surgery (19). The survival rates of the two groups were not significantly different, but the tumor-free survival rate in the recurrent group was significantly lower than that in the first hepatectomy group. It was pointed out that first hepatectomy combined with portal vein tumor thrombosis was an independent factor of poor prognosis after secondary hepatectomy, and the majority of secondary recurrent tumors after first hepatectomy were due to intrahepatic spread rather than multicentric occurrence (20). Zhou et al. reported 147 cases of subclinical recurrent intrahepatic carcinoma resected, of which 71 were resected by tumor reduction and second stage resection. To summarize the factors affecting long-term survival of hepatocellular carcinoma are (i) early diagnosis and radical resection; (ii) local resection instead of lobectomy; (iii) re-excision of subclinical recurrent carcinoma; and (iv) resection after reduction for other unresectable hepatocellular carcinoma (second-stage resection) and tumor reduction (3). Postoperative extrahepatic recurrent carcinoma is often noticed only when the lesion grows to a certain extent and becomes symptomatic, and most of them seek medical attention late, so the efficacy of surgery is not as good as that of intrahepatic recurrent carcinoma. Chen Han reported 30 cases of extrahepatic metastases resected, and the metastases appeared on average 21 months (1 month-10a) after the first hepatectomy. The survival rates were 89.7%, 61.0%, and 32.6% for 1, 3, and 5a after primary hepatectomy, respectively, and 75.4%, 29.0%, and 15.6% for 1, 3, and 5a after secondary metastasectomy, respectively. In this group, abdominal metastases (n=15) were the most common, while pulmonary metastases had the best outcome (21). Therefore, if extrahepatic metastases appear after hepatocellular carcinoma surgery, the chance of surgical resection should not be abandoned, and resection of single extrahepatic metastases can also achieve symptom relief and cure. Reoperative resection of recurrent liver cancer foci is an effective method to improve the long-term survival rate of liver cancer after surgery.3.2 Non-operative treatment of primary liver cancer with chronic hepatitis, cirrhosis, poor liver function, as well as multifocal lesions and vascular invasion, makes the proportion of re-excision in the treatment of all liver cancer recurrences still very low (about 25-35%) (22-23). Therefore, choosing a method that can protect liver function while allowing local tumor treatment is an issue that deserves attention.Lin pointed out that nonsurgical treatment methods provide more room for clinicians to develop treatment plans for recurrent cancer. The recent efficacy of transhepatic artery embolization (TAE) is good, but the long-term survival rate is not significantly improved by TAE treatment, and TAE therapy is also affected by local tumor infiltration, low blood supply status of the tumor, too large or too small, which makes the efficacy difficult to be sure. Poor liver function, deep-seated lesions or multiple intrahepatic recurrent lesions are indications for TAE therapy (24). The literature demonstrates that preoperative TACE (transcatheter hepatic artery chemoembolization therapy) and adjuvant chemotherapy after resection for resectable hepatocellular carcinoma increase postoperative recurrence and decrease the five-year survival rate (6-7). Wu Mengchao reported 109 cases of recurrent intrahepatic carcinoma with tumors straight through 0.7-15.2 cm (mean 4.6 cm) treated with percutaneous alcohol injection (PEI), with postoperative survival rates of 85.9%, 44.0%, and 19.0% for 1, 3, and 5a, respectively. PEI is the most widely used method with the best efficacy; the clinical validation of local injection treatment with acetic acid, OK-432, interferon and antitumor drugs is not superior to alcohol injection, but PEI is not suitable for patients with hepatocellular carcinoma combined with coagulopathy or ascites (19). At present, there is no breakthrough in various non-surgical treatments for hepatocellular carcinoma, and the efficacy of the combination of multiple local treatments is more optimistic. The emergence of anti-vascular drugs such as metalloproteinase inhibitors and VEGF-neutralizing antibodies has provided new ideas for the treatment of metastatic recurrence of hepatocellular carcinoma, and the development of vascular drugs is promising (25). In addition, the natural antitumor substance oxolysine (OXL) is considered to have both direct anticancer and immunomodulatory activities, and may have potential for development in the treatment of hepatocellular carcinoma (26). In conclusion, for recurrent metastasis after radical resection of hepatocellular carcinoma, comprehensive postoperative anti-recurrence therapy, early detection of recurrent foci, and timely management of recurrent foci are three key aspects to improve long-term survival (19). Recurrent metastasis of primary hepatocellular carcinoma involves both monocentric and multicentric origins of hepatocellular carcinoma and involves various factors such as oncogenes, growth factors and their receptors, tumor vasculature, and organism immunity. The early diagnosis of recurrent metastasis of liver cancer relies on the study of the malignant biology of liver cancer; in the treatment of recurrent metastasis of liver cancer, the tolerance of liver reserve function to repeated, sequential and invasive treatments is the basis for the achievement of efficacy. Further improvement of the overall efficacy of hepatocellular carcinoma remains dependent on the advancement of basic research on hepatocellular carcinoma. Biological therapies are an important aspect, among which anti-tumor vascular therapies are more promising. The prognosis of liver cancer will improve with the understanding of its biological characteristics, clinical behavior and diagnostic and treatment approaches.