Tumour site is a risk factor for hepatocellular carcinoma after hepatectomy: a 1:2 propensity score matching analysis

According to the latest cancer epidemiology survey, liver tumours are the fourth most deadly malignancy in the world, causing 841,080 related deaths in 2018 worldwide [1]. In addition, the death toll from liver tumours continues to rise, and this number is expected to increase to more than one million by 2030 [2]. As the most common malignant tumour, accounting for more than 90% of liver tumours, hepatocellular carcinoma (HCC) has many treatment options [3].

Currently, there are many ways to treat HCC, including hepatectomy, liver transplantation, local ablation and external radiation, transarterial therapies and systemic therapies [4, 5]. Among them, hepatectomy is widely practised in the treatment of HCC and is still an effective radical treatment for select patients [6‐8]; however, the 5-year recurrence rate after HCC resection can be more than 70% [9], indicating that the high recurrence rate after surgery greatly limits the treatment of HCC [10]. Many risk factors have been widely reported and recognized for HCC prognosis, such as MVI, tumour size, and tumour number [11‐13]. Among the numerous risk factors for recurrence, the relationship between the location of HCC and tumour recurrence has not been fully discussed. Whether there is a difference between the prognosis of left liver cancer and right liver cancer has been rarely discussed. The purpose of this study was to investigate whether the location of HCC affects the prognosis of liver cancer.

We retrospectively collected data from 856 patients who underwent hepatectomy at West China Hospital from 2008 to 2015. The diagnostic criteria for HCC referred to the American Association for the Study of Liver Diseases and EASL clinical practice guidelines: Management of HCC [4, 5]. Radical resection of HCC was defined as complete excision of the tumour with clear microscopic margins and no residual tumours demonstrated by computed tomography (CT) scan or angiography at 1 month after surgery [14]. The patients were divided into the left tumour resection group (L group) and the right tumour resection group (R group) according to the site of liver resection. To avoid bias, 1:2 propensity score matching (PSM) analysis between the two cohorts was performed [15]. The inclusion criteria were as follows: 1. patients without other treatment before hepatectomy; 2. hepatectomy limited to only the left or right liver; 3. patients with Child–Pugh stage A or B; and 4. patients with normal cardiopulmonary function and could withstand surgery. The exclusion criteria were as follows: 1. patients with a positive resection margin; 2. patients with recurrence within one month after the operation; 3. Patients who died within three months after surgery; 4. Patients with other malignancies; 5. Patients infected with HCV; and 6. Patients who underwent preoperative radiofrequency ablation or other intraoperative adjuvant treatments. Our study was approved by the West China Hospital of Sichuan University Biomedical Research Ethics Committee.

Although many risk factors have been widely reported to influence survival, few previous studies have reported the effect of the location of primary HCC lesions. Previously, surgeons’ understanding of liver anatomy was mainly for the innovation of the surgical method of liver resection. However, with the gradual deepening of understanding, the influence of anatomy on the prognosis of HCC should also be considered. In this study, we enrolled a large group of patients and analysed the relationship between the location of the primary HCC lesion and the survival of patients. We found that the postoperative recurrence rate and long-term mortality rate of the L group were significantly higher than those of the R group.

At present, late recurrence of HCC is generally considered 2 years after surgery [16, 17], while 5 years is usually regarded as the time point for long-term survival [18, 19]. The risk factors of early and late prognosis of HCC after hepatectomy are different and these issues have been discussed by many studies. Imamura et al. conducted research shows that factors related with elevated carcinogenesis, like higher grade of hepatitis activity, multiple tumours, and gross tumour classification, contributed to late phase prognosis [20]. Wu et al. found high viral loads and hepatic inflammatory activity were associated with late recurrence [21]. Zhang et al. revealed compared with women, men had greater late recurrence rate and rate of cancer-specific mortality [22]. From the perspective of liver anatomy, there are different structural systems of left and right hepatic venous outflow. First, most of the left hepatic vein and the middle hepatic vein converge before returning to the inferior vena cava, while the right hepatic vein exists independently [23, 24]. Fang, C. et al. conducted 3D reconstruction of hepatic veins in 200 patients and found a common trunk for the left hepatic and middle veins [25]. These main channels of venous outflow after hepatectomy may be affected to varying degrees among tumour locations, thus causing different degrees of liver congestion. Second, in addition to the different outflows of the main hepatic veins, there were significant differences in the distribution of short hepatic veins between the left and right liver. Mehran R. et al. divided the main short hepatic veins of the liver into four categories, most of which drained the right liver but not the left liver [26]. Furthermore, Sakaguchi et al. specifically analysed intrahepatic venovenous shunts of the right liver by hepatic venography [27], indicating that the right liver usually has a larger number and diameter of short hepatic veins.

The difference in the distribution of the main hepatic vein and the short hepatic vein can cause the difference in the left and right hepatic vein return. At present, whether there is a clear relationship between hepatic congestion and the prognosis of HCC after hepatectomy has not been reported in large numbers of patients, but liver congestion is widely regarded as a risk factor for the recurrence of liver tumours after liver transplantation and the survival of patients [28‐30]. Although there is no direct evidence to prove it at present, it has been found in clinical observation that liver congestion after left liver surgery is more serious than that after right liver surgery.

This study has some limitations. First, objectively evaluating liver congestion at present is difficult, and the direct relationship between congestion and tumour prognosis needs to be confirmed by follow-up studies. Second, due to the retrospective nature of the data, many missing clinical data points could not be remedied, and important gaps remain in our knowledge of this process. The results need to be confirmed by prospective studies.

Tumour anatomic location has a significant impact on the recurrence and long-term survival of HCC patients after hepatectomy, while it does not seem to affect the short-term survival of patients.