Despite patients with BCLC early-stage HCC generally present better prognosis relative to patients with late-stage HCC, a considerable number of patients still suffer from recurrence and metastasis. The presence of MVI is accepted worldwide as one of the most powerful predictors of poor prognosis in patients with early-stage HCC [4, 8, 9]. Furthermore, recent studies have found that the grade of MVI is closely related to postoperative recurrence, especially early recurrence [8, 10–13]. Of the two most used pathological staging systems for HCC, neither includes MVI as a criterion. A predictive model based on the MVI grading system for recurrence, especially early recurrence in patients with early-stage HCC, has not been reported. Therefore, we established nomograms based on the MVI grading system for recurrence and OS in patients with early-stage HCC after curative sugery, and further validation showed good agreement between the nomogram predictions and actual observations in terms of the predictive probability. In addition, our nomograms had greater predictive performance than the two classical staging systems, the BCLC and AJCC staging systems.
The prognosis of patients with HCC is mainly affected by: (1) patient factors, such as immune function, nutritional state, liver function, and status of hepatitis virus infection; (2) tumour factors, such as tumour diameter, MVI classification, and satellite nodules; and (3) factors of treatment, in particularly adjuvant treatment after surgery. In our study, nine of the twelve risk factors associated with recurrence or OS were patient factors, including neutrophil, monocyte, ALP, PAB, MCH, Urea, LDL, Apo-A1, and TT levels, while three factors were tumour-related factors including tumour size, MVI classification, and AFU. These results indicate that the prognosis of HCC is a multifactorial and complex process.
As the histopathological types and grades of MVI represent the histopathological changes that occur when a cancer embolus in a vessel evolves to become a satellite lesion or a metastatic site, the histopathological type of MVI can be used as a morphological marker to evaluate the biology and progression of HCC [4, 14, 15]. Whereas, the detectability rate of MVI is low, ranging from 12.4–33.1% in patients with early-stage HCC, and the prognositc value of MVI for patients with early-stage HCC after curative surgery remains disputable [16–18]. In our study, MVI was an independent risk factor related to DFS and OS (Fig. 1, P < 0.001) with a detection rate of 39.1% (275/703). It is generally known that tumour size is related to patient prognosis; the presence of tumour enlargement predicts poor prognosis in patients with HCC. The cut-off value of tumour size is widely used in different guidelines to predict prognosis as the relationship between tumour size and poor prognosis in patients is not linear. In this study, the cut-off values were set as 5 and 10 cm. Our study identified tumours with a diameter > 10 cm as a significant risk factor for recurrence. Interestingly, although AFP is known as a typical clinical marker for the diagnosis and prognosis of patients with HCC, it was not an independent factor related to prognosis in early-stage HCC after curative hepatectomy in our study. This may be due to the low sensitivity of AFP in predicting the prognosis of early-stage HCC. It has been reported that AFP cannot be detected in 30–35% of patients with primary HCC, while an increased AFP level is also found in those with normal health [19]. Of note, AFU was a significantly independent factor correlated with OS in early-stage HCC. It is reported that AFU is a specific marker for HCC, which exhibits higher sensitivity and specificity than AFP in diagnosing HCC. In particular, AFU is highly and accurately discriminative of AFP-negative and early-stage HCC. Therefore, dynamic monitoring of AFU is of great significance for the diagnosis and prognosis of early-stage HCC [20].
Previous studies have reported that immune function and nutritional status are related to the prognosis of patients with HCC [21–25]. In our nomogram models, neutrophil, monocyte, MCH, PAB, and urea (the final product of protein metabolism) are powerful immune and nutritional indices that can be used to predict prognosis. The prognosis of patients with low neutrophil and urea levels (indicating insufficient protein intake) is poor. The tumor microenvironment plays an important role in tumorigenesis. Immune and nutritional status, being part of tumour microcirculation, undoubtedly affects the prognosis of patients with HCC. Increasing evidence shows that basic nutritional status and systemic inflammation are related to the long-term prognosis of cancer patients [21, 26–28]. Malnutrition and low immune function not only affect the treatment effect in patients with malignant tumours, but also make patients with HCC more prone to relapse and metastasis [21].
In recent years, metabolic disorders, especially lipid metabolism disorders, have emerged as an important microenvironment for HCC pathogenesis [29, 30]. LDL and Apo-A1, as indices of liver lipid metabolism, served as significant predictors for the prognosis of early-stage HCC in this study. It is known that changes in the metabolism of liver lipids are closely related to the occurrence of liver cancer, and in the future, non-alcoholic fatty liver disease may be identified as one of the main causes of primary liver cancer [31]. Moreover, previous studies have also shown that lipid metabolism disorders can promote tumour cell proliferation by inhibiting the apoptosis of liver cancer cells, resulting in a poor prognosis [32].
Yet, there is still room for further improvement. First, our model is primarily based on retrospectively collected datasets from two Chinese institutions. Although the models performed well, the inclusion of additional cohorts from other institutions may improve the predictive accuracy of our model. Second, though the sample size in this study is adequate, a larger sample size in conjunction with meaningful information including postoperative adjuvant treatment collected in the future may improve the accuracy of our results. Third, hepatitis B virus (HBV) infection, known to be associated with a poor prognosis of HCC, showed limited prognostic value in our study. This may have been due to some patients receiving non-standardized anti-HBV treatments, which may have affected the statistical results.