The reasons for high mortality from liver cancer are certainly related to the difficulty of early detection and the lack of effective radical means for patients with intermediate to advanced disease; but more importantly, tumors are still prone to recurrence after radical resection, with an overall 5-year recurrence rate of nearly 70%.
There are two mechanisms thought to exist for recurrence of liver cancer after radical resection:
- The tumor is highly aggressive, gradually invading the large portal vein, hepatic vein, and even the biliary system from the adjacent microvasculature, and then disseminating throughout the liver, lung, and body, involving multiple links and steps.
- From the multiple origins of hepatocellular carcinoma theory, recurrent foci are considered to be of new origin and different from the primary foci DNA fingerprints. In this way the study returns to the origin of liver cancer: cancer-inducing and cancer-promoting factors.
There are many factors that influence recurrence of hepatocellular carcinoma after surgery, and we address each in terms of tumor, patient, and treatment modality.
Tumor factors
Tumor factors are at the core of the host-tumor paradox. Pathological characteristics of the tumor, such as size, number, degree of tumor differentiation, and vascular invasion, are important factors affecting the patient’s prognosis.
Domestic and international guidelines for the treatment of hepatocellular carcinoma include tumor size, number, and vascular invasion in staging, determining prognosis, and developing individualized treatment plans.
Tumor size
Postoperative outcome of hepatocellular carcinoma is closely related to the size of the liver cancer. Large tumors are an independent risk factor for postoperative recurrence, and long-term survival is better for small than large hepatocellular carcinomas.
The 5- and 10-year survival rates for large liver cancers larger than 5 cm were 35.9% and 18.6%, respectively; for those smaller than 3 cm, 47.4% and 18.9%, respectively. Large hepatocellular carcinomas are prone to form satellite foci in areas away from the lesion, which in turn form recurrent foci in the early postoperative period.
Vascular invasion of the tumor
Vascular invasion of the tumor, especially microvascular invasion, is a special intermediate stage in the development of hepatocellular carcinoma, and the subsequent formation of tiny intrahepatic metastases is a direct source of postoperative recurrence.
Patient survival rates at 1 and 2 years are only 18% and 12% if a major branch of the portal system develops. 75% of patients who recur within 1 to 2 years after surgery have microvascular invasion.
Degree of tumor differentiation
The degree of tumor differentiation partially reflects the biology of the tumor, and poorly differentiated tumors tend to be more aggressive and combine with microvascular invasion.
However, as a pathologic grading index, it is difficult to quantify and there is an element of human judgment that limits its place in recurrence-related studies.
Other factors of tumor
With the development of molecular biology, a variety of molecules are thought to be potentially involved in tumor recurrence and metastasis. p53 mutations, H-RAS, epidermal growth factor receptor (EGFR), hepatocyte growth factor (HGF) factor, HGF) as oncogenes, are positively associated with recurrence of hepatocellular carcinoma.
Hepatocellular carcinoma induces tumorigenesis through the secretion of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor (TGF), and other cytokines. The tumor vasculature is induced by a variety of cytokines, including VEGF, fibroblast growth factor (FGF) and transforming growth factor (TGF), which are involved in the proliferation of micro-metastases after surgery.
While more and more molecules are being identified, independent, core molecules have not been established. Therefore, the only widely used, widely recognized, recurrence-related tumor factors are: tumor size, number, and vascular invasion.
Patient factors
Patient factors are another central part of the host-tumor paradox. Patient gender, mental status, degree of cirrhosis, and hepatitis activity are all associated with the prognosis of patients after hepatocellular carcinoma surgery.
Gender of the patient
Hepatocellular carcinoma predominates in male patients, with a 7:1 male to female sex ratio, and long-term postoperative survival is also more common in women.
Patient mental status
The presence of a preoperative state of severe anxiety and depression in patients with hepatocellular carcinoma has been reported to be positively associated with the risk of recurrence, presumably disrupting the patient’s immune homeostasis with severe anxiety and depression.
Hepatitis activity
Many of our patients with liver cancer are combined with hepatitis, especially hepatitis B, which also increases the risk of liver cancer recurrence.
- HBV infection leads to persistent inflammation and repair of the liver, which in turn leads to cirrhosis and plays a key role in the development of hepatocellular carcinoma due to both internal and external factors, and is the root cause of postoperative multicentric occurrence of hepatocellular carcinoma.
- While providing the necessary microenvironment for the formation and development of micro-metastases after hepatocellular carcinoma surgery.
- Long-term application of nucleoside analogs not only suppressed chronic inflammation in the liver, partially reversed the degree of cirrhosis, and reduced the recurrence rate of postoperative hepatocellular carcinoma.
Treatment modalities
Surgical resection of hepatocellular carcinoma is an important tool to achieve radicality, but surgery and its associated factors may also contribute to postoperative recurrence.
Extent of surgical resection
Positive margins clearly do not meet the criteria for radical resection. However, in patients with important vessels and ducts that must be preserved, resection may be possible only along the pseudo-envelope of the tumor.
Studies have reported 1-, 3-, and 5-year survival rates of 73%, 33%, and 29%, respectively, in the margin-positive group, and 83%, 61%, and 50%, respectively, in the margin-negative group. Even with a margin width of 1 to 2 cm, satellite foci and microemboli were found in the peritumoral tissue in some patients.
However, simply expanding the resection does not ensure the eradication of satellite foci and microscopic cancer emboli, and increases the chance of postoperative liver failure, which affects the overall survival rate. Only a comprehensive consideration of the patient’s postoperative hepatic function compensability, combined with the grading of tumor aggressiveness, can select the appropriate extent of resection.
Intraoperative blood transfusion
Intraoperative blood transfusion not only increases the patient’s chance of contracting infectious diseases, but also causes a decrease in the body’s immune function, which has a facilitating effect on postoperative recurrence of hepatocellular carcinoma.
Laparoscopic techniques
With the advancement of minimally invasive laparoscopic techniques, many conventional hepatectomies have been replaced by laparoscopic hepatectomy, and some even consider laparoscopic hepatectomy to be “no surgery off-limits. The recurrence and survival rates of laparoscopic surgery are close to those of conventional resection, according to many studies.