Tumor size is a key characteristic of HCC and its classification is one of the most important issues for HCC treatment and prognosis. However, there is currently no uniform cutoff criteria for size of HCC. A systematic review showed there are three kinds of criteria for small HCC alone . Even in different stage systems, the criteria for size of solitary HCC are inconsistent. In this study, we subdivided tumor size by 1cm intervals and analyzed the relationship between tumor size and the overall survival of 1760 patients with solitary HBV-related HCC. Our results revealed a stepwise incremental deterioration in OS outcomes with increased tumor size, which is consistent with other studies [10, 11]. Then we employed minimum p value method to screen the appropriate size cutoffs that could divided HCC tumor OS well.
Many previous studies showed that multiple dichotomy can divide tumor size well based on prognosis. The BCLC, AJCC, Japan Integrated Staging Score (JIS) employ 2cm as the cutoff for single HCC [17, 18, 20], while the Hong Kong Liver Cancer (HKLC) and Chinese Liver Cancer (CNLC) staging system use a cutoff with 5cm [21, 22]. One previous study suggested multiple size cutoffs such as 2cm, 3cm, 4cm, 5cm, 8cm, and 10cm have good discrimination for HCC prognosis . In this study, similarly, dichotomy results of minimum p value of OS showed that 8 among 10 cutoffs can divide tumor size into 2 groups well. These evidences indicated dichotomy of HCC tumor size might not reflect the biological nature of HCC. Among these cutoffs, the HR values of OS are compared, 9cm has the highest HR for OS. This is inconsistent with the result of a multi-center study indicating 2cm has the highest HR for OS , which may be caused by different study population and treatment decisions in different countries or regions.
Then, we divided HCC tumors into 45 trichotomy groups. There are 8 cutoffs of size discriminated OS well when minimum p value was set at p <0.0001. With the comparison of HR of these groups, we found that 3/9cm cutoff groups have the highest HR value for OS. When we tried inquartation of tumor size, there were no cutoffs were screened. Furthermore, the comparison of clinicopathologic characteristics of new classifications showed that the increase of tumor size was associated with biological characteristics. On the basis of these results, 3/9 cm could be an appropriate size cutoff for HCC tumor.
There are some similarities and differences with other studies. In one study of 857 patients with single HCC, 5/8 cm were suggested to be cutoff of size after dividing HCC into 5 groups with 2cm intervals and combining the adjacent groups with similar OS . Another large retrospective study chose the controversial cutoff of 5 cm as the boundary of small and large HCC after similar method . As the initial criteria of small HCC, 5cm were raised since the mid to late 1970s . Along with the advances in radiographic diagnostic techniques and pathophysiology, smaller criteria such as 3cm and 2cm were proposed to replace the criteria of small HCC by many East-West study groups. The size cutoff of 2cm was raised from BCLC system in 2003 based on the data of the Liver Cancer Study Group of Japan (LCSGJ) and has been adopted in the BCLC and AJCC staging system (Eight Edition). However, many studies showed tumor up to 2cm are accounted for a very small proportion of HCC and hard to analyze their pathobiological characteristics . Moreover, studies based on pathobiological characteristics indicated that 3cm in diameter is an important turning point of HCC development, where HCC transformed from relatively benign behavior to a more aggressive progression . From a clinical standpoint, single HCC tumors up to 3cm had a similar 3-years OS rate when treated by radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) and surgical resection . Thus, 3cm as a cutoff of small HCC had a pathobiological and treatment significance.
With the development of research, the cutoff of large HCC tumor size was no longer confined to 5cm, which can be reflected in changes in criteria for liver transplantation. University of California, San Francisco (UCSF) criteria  and Up-to-Seven criteria  implied single tumors ≤ 6.5 or ≤ 6cm had a same prognosis with Milan criteria. Hangzhou criteria  and Fudan criteria  further broadened the size cutoff of single HCC tumor to 8cm and 9cm. In this study, we reclassified patients into three new classifications: ≤ 3cm, > 3 and ≤ 9cm, and > 9cm according to the results of minimum p value of OS. The comparison of clinicopathologic characteristics among these three groups showed that increase of tumor size was associated with multiple pathobiological features such as AFP, MVI, tumor differentiation, and liver cirrhosis. In addition, the comparison of the overall survival between any two subgroups showed a statistical difference (all p<0.001). These indicated that 3/9cm as the boundary of small HCC and large HCC had a biological meaning and prognostic significance.
There are a few limitations to this study. Firstly, although the study population is large enough, this is a retrospective study and thus the results may not be generalized. A multicenter prospective study may be necessary to perform to validate our results. Secondly, all of the study population was HBV related HCC since their characteristics are different from non-HBV related HCC. Thirdly, insufficient patient volume of HCC ≤ 1cm may lead to be hard to work out further subclassification of HCC tumor size.
In conclusion, this study suggested that the tumor size with a cutoff of 3cm and 9cm in solitary HBV related HCC patients were appropriate based on biological characteristics and prognostic significance.