For patients with HCC who underwent resection surgery, tumor factors, viral factors and the degree of liver functional reserve were associated with recurrence [7
]. We recently found that tumor factors were predictive of early recurrence within 2 years after surgery, while viral factors and “field factors” in non-tumor parts influenced late recurrence [19
]. The impact of field factors may be overwhelmed by the tumor factors in advanced HCC. From the current study, univariate analysis revealed that age, serum AST, APRI, AFP levels, platelet counts, as well as Ishak inflammation scores and the degree of fibrosis in non-tumor part were associated with overall survival. Additionally, age and APRI levels were the independent risk factors by multivariate analysis. It demonstrated that the confounding effect of tumor factors was minimized, and background liver fibrosis played a more important role in the prognosis for patients with small and solitary HCC. Consequently, it is implied that treatment to attenuate fibrosis might help to decrease recurrence for such patients. It may be a target for adjuvant therapy after surgery.
Adachi et al. [24
] found that serum albumin and ALT levels were independent risk factors associated with recurrence in patients with small HCC who underwent resection surgery. Tumor factors, such as size, histological grade and AFP levels, were not significant in their study. It was demonstrated that liver reserve, but not tumor factors, was the predominant factor for predicting recurrence of small HCC. However, platelet count, ICG-15R and cirrhosis were not significant in predicting recurrence. This could be due to the fact that the majority of patients in their cohort were cirrhotic in non-tumor areas. The mean values of platelet count were lower (91,000 vs. 146,315/mm3
) and ICG-15R values were higher (17.7 vs. 14.7%) than in our patients. This would imply that the stages of fibrosis in their patients were more advanced. Consequently, the effect of fibrosis on tumor recurrence might be diminished in the statistical analysis due to the limited number of patients with early stage fibrosis in their study. Moreover, they did not provide data for patients with minimal fibrosis; therefore, we could not evaluate the role of minimal fibrosis in recurrence from their study. Additionally, only 20.6% of patients in their cohort had chronic hepatitis B. The diversity between etiologies, stages of fibrosis and degree of liver reserve in these two studies might account for the discrepancies. However, both our group and Adachi demonstrated that “field factors” play an important role in determining tumor recurrence in patients with small HCC who underwent resection surgery.
Liver biopsy is the gold standard for the assessment of liver fibrosis for patients with chronic hepatitis. However, it is costly and carries risks of complications such as pain, bleeding, hemothorax, bile duct injury or penetration of abdominal viscera. Also, sampling errors and inter-observer variation decrease the reliability of liver biopsy [25
]. Recently, several noninvasive serum markers were used as surrogates for evaluating the stage of liver fibrosis in chronic hepatitis patients. However, these markers are less widely used for patients with HCC. Previous studies demonstrated that the presence of cirrhosis or portal hypertension was not an independent risk factor of mortality or developing recurrence after surgery for small HCC [24
]. However, they only evaluated the impact of cirrhosis and advanced fibrosis on the post-operative prognosis. The novelty of the current study is that we assessed the role of minimal fibrosis in the prognosis of patients with small solitary HCC who underwent resection surgery. Additionally, we provide an easy and feasible tool, APRI, which not only exhibits greater discriminative ability for the stage of liver fibrosis than other serum markers, but also predicts recurrence and survival for patients with small HCC. We expect it would help clinical physicians to predict outcomes before resection and to arrange adequate antiviral therapy after surgery for such patients.
We acknowledge several limitations in this study. First, the patients enrolled in this study were all infected with HBV. For HCC patients from other etiologies, both the impact of fibrosis and the application of APRI for assessing the stage of fibrosis and predicting outcomes need further prospective study with more patients to be elucidated. Second, the number of patients enrolled in our cohort is relatively small. Although minimal fibrosis is closely related to better overall survival for patients with small and solitary HCC by univariate analysis, it failed to predict outcomes in multivariate analysis. However, APRI was an independent risk factor to be associated with overall survival. If APRI was not enrolled in the multivariate analysis, the degree of hepatic fibrosis was still an independent risk factor to predict survival. It may be attributed to the following: APRI not only serves as a surrogate for assessing the degree of hepatic fibrosis, but also reflects liver functional reserve [28
] causing minimal fibrosis, which was excluded by multivariate analysis. Accordingly, APRI is a simple and powerful predictor of prognosis for patients with small HCC who underwent resection surgery.
Several newly developed noninvasive serum models, such as FibroTest, the European liver fibrosis test, FIBROSpect, Hepascore and FibroMeter, have been introduced for assessing the stage of liver fibrosis in chronic hepatitis patients [17
]. As this is a retrospective study, another limitation of our study is that we could not compare the APRI to these new models. However, these models combine several non-routine tests, including hyaluronic acid, tissue inhibitor of metalloproteinase 1, alpha-2 globulin, alpha-2 microglobulin and apolipoprotein A. They are not readily applicable in daily practice and require additional costs. Besides, they often need complicated formula. We think that APRI still has an important role in the evaluation of liver fibrosis status because it is clinically available and easy to compute. Nevertheless, further prospective studies to evaluate the application of these newly developed serum markers for predicting prognosis of patients with small HCC are still needed.
In conclusion, our study demonstrated that for small and solitary HBV-related HCC patients who underwent resection surgery, the degree of liver fibrosis is associated with tumor recurrence as well as with overall survival. APRI could serve as a surrogate for the evaluation of liver functional reserve, assessment of hepatic fibrosis and prediction of survival for such patients.