[Abstract] At the present stage in China, the professional fields related to liver cancer are gradually subdivided, the professional scope and knowledge of doctors are becoming narrower and narrower, the tendency to think and make decisions about liver cancer treatment from their own professional perspective is becoming more and more obvious, and it is difficult to form effective collaboration between disciplines. A systemic view of liver cancer is undoubtedly an important prerequisite for further improving the efficacy of liver cancer. In this article, we present the systemic view that should be taken in the decision making of liver cancer treatment from seven aspects: the essence of medicine, changes in clinical treatment, anatomical and functional characteristics of liver, the law of multicenter occurrence, pathology, tumor immunology and biology, aiming to provide a little reference to optimize physicians’ vision of liver cancer and clinical thinking ability. In the past two decades, the understanding of liver cancer has become more and more in-depth and systematic, the treatment means of liver cancer have gradually been enriched and matured, and the treatment principles of liver cancer have become more rational and scientific, all of which have laid a solid foundation for further improving the efficacy of liver cancer; however, in contrast, the clinical efficacy of liver cancer has not been substantially improved as a result. One is that there are many factors affecting the development of hepatocellular carcinoma, and we know little about them; the other is that the professional fields related to hepatocellular carcinoma treatment are gradually subdivided, and the professional scope and knowledge of physicians are becoming narrower and narrower. As a result, it is difficult to form effective collaboration among disciplines, and the potential advantages in theory and method cannot be translated into improved efficacy, and there is a certain degree of disconnection between theory and practice. The richer the theories, the more diverse the techniques and the more refined the specialties, the more doctors need to have a systematic understanding and grasp of the theoretical systems and technical methods related to liver cancer, and on this basis, collaboration, complementation and integration among disciplines. Only in this way can we see more fully, think more and do better in liver cancer. In this paper, we would like to briefly discuss the systemic view in liver cancer treatment decision making, aiming to provide some reference for optimizing physicians’ liver cancer vision and clinical thinking ability. 1. Humanistic needs of liver cancer patients from the perspective of medical essence Medicine is a natural manifestation of human nature and natural behavior to maintain and promote human physical and mental health and vitality. The essential characteristic of medicine is humanistic care, which is the care of life state, the maintenance of life dignity and the respect of life value. This is both the starting point and the ending point of medicine. With the development and progress of medicine, doctors have become more and more technically competent and can perform more and more major traumatic surgeries, and along with this, the tendency of both doctors and patients to worship technology has become more and more obvious, and the potential harm of technology to patients has become more and more significant. In this context, it is undoubtedly of great practical significance to always think about the essential characteristics of medicine, pay attention to the humanistic needs of liver cancer patients for treatment decisions, and constantly use them to lead liver cancer clinical practice. Grasping and respecting patients’ psychological needs is one of the important aspects of humanistic care. Due to different social status, family situation, age, gender and personality, patients with liver cancer often have different psychological responses to the disease and psychological needs for treatment. Some patients are willing to take greater treatment risks and undergo highly invasive surgeries, such as extensive liver resection and liver transplantation, for better outcomes, while some patients are reluctant to undergo surgical treatment and tend to choose minimally invasive treatment means. It is worth emphasizing that due to information asymmetry, patients’ psychological needs can only be used as one of the bases for physicians to make treatment decisions. When deciding on treatment, the patient’s psychological needs should be considered on the one hand, and the safety and efficacy of the treatment should be considered on the other. Only when these two aspects are considered together can the resulting treatment plan be most beneficial and easily accepted by patients, and a one-sided emphasis on either aspect would be biased. The characteristics and indications of various treatment methods for hepatocellular carcinoma from the perspective of historical changes Reviewing, summarizing and reflecting on history can make us more rational and wise. Looking at the development of clinical treatment of liver cancer in the past half century, it seems that we can still truly feel the pioneering innovation and aggressive efforts of our predecessors. In order to treat liver cancer, we should be familiar with the history and changes of various liver cancer treatment methods and treatment concepts, and be able to accurately and rationally grasp the characteristics and indications of each treatment method from the historical condensation. Only in this way can we avoid the blind admiration of physicians for their own expertise and prejudice against other expertise to the greatest extent. In the battle against hepatocellular carcinoma, hepatectomy is a veritable “vanguard”. More than half a century ago, hepatectomy became the only means to cure liver cancer due to the advancement of liver anatomy and liver cancer pathology. In the 1970s, the use of fetoprotein testing in clinical practice greatly improved the early diagnosis rate of liver cancer, expanded the scope of hepatectomy, and improved the clinical efficacy. The successful implementation of treatment modalities such as transarterial vascular intervention (chemo)embolization (TACE/TAE) and percutaneous percutaneous anhydrous alcohol injection (PEI) has pioneered minimally invasive treatment of liver cancer, allowing patients who are unable or unwilling to undergo surgical treatment to receive effective treatment. The local treatment of liver cancer represented by radiofrequency ablation (RFA), after 20 years of development, has become a minimally invasive and inexpensive means to cure liver cancer, and its long-term efficacy is similar to that of surgical treatment for early-stage liver cancer. Liver transplantation, a complete treatment for both liver cancer and cirrhosis, has evolved the concept of complete removal of liver cancer to the extreme, enabling patients with poor liver function but early stage liver cancer to receive curative treatment. In recent years, chemotherapeutic drugs represented by sorafenib have enhanced the efficacy of advanced liver cancer to a certain extent. The above treatments are imprinted with different colors of the times and represent different treatment concepts. At present, there is a fierce collision and integration of various liver cancer treatment concepts, which will inevitably lead to the sublimation of liver cancer treatment concepts and reconstruction of treatment modes. The liver is located at the center of the “intestine-liver-lung” axis, and is the important “blood channel” responsible for the return of blood from the stomach, intestines, pancreas and spleen to the heart. It is an important “blood channel” for the return of blood from the stomach, intestines, pancreas and spleen to the heart. In cirrhosis, the vascular structure in the liver is compressed and deformed, and the portal blood flow is blocked. At the same time, the liver is also an important metabolic organ that nourishes and maintains life, supporting the body’s metabolism, detoxification, immunity and other important functions. In chronic liver disease or even cirrhosis, the functional reserve of the liver is significantly reduced. When treating liver cancer, if we do not take extra care of the already low level of liver reserve function, it will induce serious damage or malfunction of other important organs such as liver, which will have systemic adverse effects on the organism. Numerous studies have shown that postoperative liver function status and portal vein pressure level are important prognostic factors in the treatment of liver cancer. When deciding the treatment plan for hepatocellular carcinoma, the intrahepatic venous blood channel and liver function reserve should be fully evaluated, and scientific predictions should be made for these two important indicators after treatment to ensure the smooth return of blood from the portal venous system and the smooth compensation of liver function after surgery. Otherwise, even if the liver cancer is removed “cleanly”, the efficacy and quality of life will not be guaranteed. To sum up, the fundamental principle of liver cancer treatment is to remove the lesion under the premise of maintaining the structure and function of liver to the greatest extent, which is the “cancer-based treatment” under the premise of “liver-based treatment”. The establishment of this concept is the reason why minimally invasive treatments such as RFA and liver transplantation have been highly recommended in the past decade or so, while the application of hepatectomy has become narrower and narrower. 4. Stages of hepatocellular carcinoma development from multicentric occurrence pattern The understanding of multicentric occurrence of hepatocellular carcinoma is an important progress in understanding hepatocellular carcinoma in recent years. The literature reports that among 94 hepatic resection specimens with less than 3 cm diameter HCC, 9 (9.5%) cases had simultaneous multicentric occurrence lesions and 7 (7.4%) had adenomatous hyperplasia, implying an incidence of at least 7.4% for heterochronic multicentric occurrence lesions; among the livers of 8 patients with small nodular cirrhosis, 4 (50%) had multicentric hepatocellular carcinoma. 14 patients who met the Milan criteria for hepatocellular carcinoma after liver transplantation, 34 lesions were found in the liver of 9 (64.3%) patients. Data from China [16] showed that among 83 patients with multifocal hepatocellular carcinoma, 16 (19.5%) cases were diagnosed with multicentric raw lesions. The presence of heterochronic multicentric lesions and the presence of a certain rate of missed diagnoses on CT and MRI lead to a potentially multistage progression of hepatocellular carcinoma. This also means that it is difficult for imaging to see all the existing lesions where they are located, and what is shown may only be a part of the real-time lesions; even if imaging examinations have seen all the existing lesions, in terms of the developmental process of liver cancer, only one stage of liver cancer is seen. This is like looking at a train through a doorway; when the doorway is narrow, only one window of one train car can be seen; when the doorway is wider, what can be seen is only one or several complete carriages, not the whole train. 5. Scope of hepatocellular carcinoma from pathological viewpoint For a single hepatocellular carcinoma lesion, its pathological scope includes at least three parts: main carcinoma foci, peri-cancerous micro-venous infiltration foci and satellite foci. Generally speaking, the lower the degree of differentiation of hepatocellular carcinoma, the larger the cancer foci, the wider the scope of microvenous infiltration area, and the more satellite foci and the more distant from the main cancer foci. The study showed that among 48 cases of small hepatocellular carcinoma with diameter ≤3 cm, 16 cases (33.3%) had satellite foci; among them, 12 cases (75.0%) had satellite foci ≤1 cm, 3 cases (18.8%) had satellite foci 1-2 cm and 1 case (6.3%) had satellite foci >2.0 cm from the main carcinoma; among 65 cases of hepatocellular carcinoma with diameter >3 cm, 39 cases (65.0%) had satellite foci; among them, the Sasaki et al. studied 100 cases of hepatocellular carcinoma ≤5.0 cm in diameter and found that 46 cases (46.0%) had satellite foci with a mean distance of 1.0 cm (median 0.5 cm) from the main foci. Since most of the satellite foci and all of the microvenous infiltration foci could not be revealed by imaging data, the imaging extent of hepatocellular carcinoma differed significantly from the pathological extent. In conclusion, when looking at hepatocellular carcinoma clinically, usually only one stage and part of the hepatocellular carcinoma is seen, far from the whole hepatocellular carcinoma. Unless liver transplantation is performed, liver cancer is usually difficult to eliminate completely. When formulating the treatment plan, the possibility of multicenter occurrence of liver cancer, potential metastatic lesions, as well as peri-cancerous micro-venous infiltrative lesions and satellite foci should be considered in an integrated manner, focusing not only on removing the lesions to the greatest extent possible, but also on performing multi-stage sequential treatment for patients. Tactical attention and strategic preparation are required. Another point of pathological perspective for treatment decision of hepatocellular carcinoma is the arterial blood supply of hepatocellular carcinoma. The degree of hepatocellular carcinoma blood richness is much more significant for local ablation treatment than for surgical procedures. The arterial blood supply of hepatocellular carcinoma is the most important pathological histological basis for the efficacy of TACE/TAE, and those with rich arterial blood supply have strong indications for TACE/TAE and good efficacy, and vice versa. As for RFA, because arterial blood supply can produce “heat sink” effect, when arterial blood supply is rich, residual cancer foci are likely to occur. For cancer foci with rich blood supply, transarterial vascular embolization before ablation treatment can effectively reduce the “heat sink” effect and improve the ablation efficiency and efficacy. 6. Immunological orientation of liver cancer treatment from the perspective of tumor immunology Modern tumor immunology believes that the occurrence and development of liver cancer are closely related to the immune status of the body. There are two extremes in clinical practice that are sufficient to support this point: the growth of liver cancer is usually slow in the initial or young stage, probably due to the immune escape ability of liver cancer and the immune surveillance ability of the body in a state of stalemate, and the tiny lesion stage can last for months or even years; after liver transplantation for liver cancer, the rapid growth of potential metastases outside the liver can occur due to the suppressed immune function of the body. The ideal liver cancer treatment plan can not only completely eliminate the tumor, but also maintain or promote the body’s immune function. The three currently recognized curative treatments for liver cancer – liver transplantation, hepatectomy and RFA – have quite different effects on the body’s immune function. After liver transplantation, immune function is artificially suppressed to avoid immune rejection. At this time, as long as there is residual cancer tissue, rapid tumor progression is prone to occur, which is the most important reason for the strict requirement of liver transplantation indications for liver cancer. After liver resection, factors such as trauma, blood loss, negative nitrogen balance and reduced liver function can cause the body’s immune function to present a certain degree of depression, which can promote the growth of residual cancer foci. Antigen-presenting function, tumor-specific T lymphocyte activity, natural killer cell activity, and liver blast cell activity are all significantly enhanced, and have a significant inhibitory effect on tumors. This also implies that RFA treatment of liver cancer does not only rely on pure mechanical tumor ablation, but immune enhancement may also be an important mechanism. In recent years, some huge hepatocellular carcinomas, which are difficult to be completely resected and even more difficult to be completely removed by RFA, have obtained unexpectedly satisfactory results by repeated application of RFA, which seems to be a strong support for the above theory. 7. The diversity of hepatocellular carcinoma from a biological perspective Hepatocellular carcinoma is a genetic disease caused by multiple genetic mutations. Infiltration and metastasis are the most important biological features of hepatocellular carcinoma. The invasive metastatic potential of hepatocellular carcinoma is mainly developed at the primary tumor stage, but can be enhanced to some extent during its progression. The differences in the infiltrative and metastatic capacity of hepatocellular carcinoma have led to the diversity of clinical features and different indications for hepatocellular carcinoma. Some hepatocellular carcinomas are predominantly growth-based, with weak or even absent ability to infiltrate and metastasize. These tumors, even if they grow large, are more limited in scope and can be easily removed. While some other hepatocellular carcinomas, with strong infiltrative and metastatic ability, have obvious vascular infiltration and metastasis in the early stage, which are not easily removed completely. Of course, most hepatocellular carcinomas have an infiltration and metastatic capacity between these two extremes. Different biological characteristics of hepatocellular carcinoma may also lead to significantly different sensitivity and resistance to chemical drugs or targeted therapeutic agents, resulting in different clinical response and efficacy. In conclusion, medicine is not only scientific, but also humanistic and artistic. It is a never-ending scientific proposition to raise the level of ability to systematically understand liver cancer, to scientifically and rationally coordinate various treatments for liver cancer, and to maximize the satisfaction of patients’ needs. As far as the current level of understanding is concerned, the above seven perspectives constitute the main framework of the systemic view of liver cancer, which can be used as a grasp to further enhance the efficacy of liver cancer treatment. After all, the way of thinking itself is the productivity!