A preoperative nomogram predicts prognosis of patients with hepatocellular carcinoma after liver transplantation: a multicenter retrospective study

The incidence of liver cancer, despite showing some slow down, increased by 2–3% annually from 2007 to 2016 [1]. R0 resection and liver transplantation (LT) are regarded as the key methods for the complete remission of liver tumors [2, 3]. LT replaces the diseased liver while simultaneously providing complete oncological resection, which represents a predisposing factor in greater than 90% of patients with hepatocellular carcinoma (HCC) [4].

Over the last 20 years, various criteria incorporating preoperative variables have been formulated to limit the selection of patients with HCC for LT [5‐8]. In 1996, the Milan criteria (MC) were introduced and have been used widely ever since. The MC limited LT to patients with a single tumor with a diameter up to 5 cm diameter or up to three tumors, none of which is larger than 3 cm [5]. Twelve years later, the Hangzhou Experience (HZ) was established by our group, which had wider surgical indications than the MC and was more suitable for Asian populations [6]. Thereafter, criteria for postoperative guidance were lacking until Agopian et al. reported a prognostic system that could accurately predict HCC recurrence after LT [4]. Unfortunately, this model focused on HCC recurrence and was constructed on Caucasian population data. Therefore, we established this large, multiple-center retrospective study comprising Chinese patients with HCC who underwent LT at three liver transplantation centers in China. The study aimed to formulate a nomogram to predict the long-term survival of these patients, to guide adjuvant therapy, and facilitate personalized management.

Whether LT is the best treatment option for HCC is a matter of debate [6]. However, currently, LT is widely accepted as the best treatment modality. The introduction of the Milan criteria (MC) represented a breakthrough in the standardization of LT and the Hangzhou experiences (HZ) further broadened the indications for surgery. However, increasing evidence showed that these criteria are too conservative and only focus on the tumor status. In fact, whole body condition of patients and other parameters, such as liver function, radiological appearance, and epidemiological factors, can also affect the outcome of LT. The present study aimed to identify independent risk factors for prognosis in patients with HCC who received LT. These risk factors were then used to establish a nomogram for the presurgical prediction of OS.

During the construction of the nomogram, we did not try to replace the original standards, such as the MC or HZ criteria. We included these criteria and other parameters, including laboratory results, epidemiological factors, and the previous history of the patients, but not tumor status. As expected, multivariate analysis identified the LT criteria as one of the risk factors of prognosis. Patients with tumors within the MC criteria, beyond the MC but within the HZ criteria, or exceeding the HZ criteria were given different statistical weights. Patients with tumors exceeding the HZ criteria received 45 points and had the worst prognosis because of advanced tumor and poor patient status. Initially, the MELD score was designed to evaluate renal and hepatic dysfunction-induced organ failure. However, it has been well-validated to guide organ allocation policy and to identify patients who are at risk of death because of end-stage liver disease [11]. In general, organs with a high donor risk index (DRI) should be transplanted into patients with a low MELD score of 10–14 [12, 13]. However, subsequent data showed that patients with high MELD scores could also benefit from sub-optimal organ transplants [12‐14]; therefore, we included the entire range of MELD scores into our model.

In this study, HbeAg positive was found a risk factor of OS. It was reported that the risk of HCC increased significantly when associated with a single positive HbeAg [15]. Other studies reported that persistent viremia might result in active liver disease after HbeAg seroconversion or fluctuating HBeAg status, which would increase the risk of HCC and liver cirrhosis in these patients [16, 17]. However, Chan et al. reported that compared with HBeAg positivity, HBV-DNA is a more important risk factor for HCC [18]. Unfortunately, the data on HBV-DNA was lacking in our study, which might have affected the accuracy of our nomogram. In addition, HbeAg positivity always occurs in the active phase of hepatitis. Most HCC are due to cirrhosis caused by HBeAg positive, and cirrhosis is the most important risk factor for HCC. Studies on the correlation between cirrhosis and HCC have shown that the forming procession of HCC is largely mediated by inflammation, which causes the cycle facts of cell death and regeneration and induces the repeated proliferation of liver cells [19]. The release of inflammatory factors and poor patient status will also affect the result of LT. Hepatitis B X protein (HBx) is encoded by HBV, and it has been demonstrated that HBx is closely linked to HBV-related HCC [20]. HBx plays a multifunctional role in common biochemical pathways by modulating the expression and activities of numerous genes, contributing to many pathological processes, including viral replication, gene transcription, signal transduction and protein degradation, which are ultimately linked to the occurrence and development of HCC [21, 22].

Studies have shown increased prevalence of antibody-mediated rejection and cholangitis, lower graft survival and hepatic artery thrombosis in ABO- unmatched LT compared with those in ABO-matched LT. These observations could explain the results of the present study. In addition, a meta- analysis also showed worse graft survival in ABO- unmatched LT compared with that in ABO- matched LT [23]. When the blood type of A, B and O are incompatible, the antibody of anti-A or B in recipient’s blood will combine with the antigen directly, which is on the vascular endothelial cells of graft, and produce an antigen-antibody complex, activate the complement system quickly. As a result, it will destroy the vascular plexus and small bile ducts in the graft, form the extensive thrombotic microangiopathy, cause a series of rejection reactions and complications. The above factors will reduce the survival rate of the graft [24].

This study has some limitations. First, our study included four clinical indicators and no biological ones. Second, despite having 269 patients in this study, the validation cohort had a relatively small sample size, which might have resulted in its high C-index (0.874). Similarly, due to the limited samples size in the high-risk group and there are only two long-term survivors after 20 months, it may cause our nomogram to have a certain deviation in the assessment of 24 months and 36 months. Larger-sized cohorts are required to further determine the clinical value of the nomogram. In addition, the C-index will become more accurate with the expansion of the sample size. Second, as stated above, the lack of HBV-DNA data might have influenced the application value of our model, and we hope to fix this problem in future.

A novel nomogram for OS prediction of patients with HCC after LT was constructed based on four essential independent risk factors determined at diagnosis. This nomogram showed good performance, with a C-index = 0.874 for the external validation cohort. The model allowed us to classify patients with HCC after LT into three risk groups. The identified risks could be used to provide specific management strategies in the future.