A proposal for T1 subclassification in hepatocellular carcinoma: reappraisal of the AJCC 8th edition

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and 6th most common cancer worldwide, with an estimated death of approximately 830,000 worldwide in 2020 [1‐4]. In Taiwan, it is the fourth most common cause of cancer death and causes more than 7000 deaths each year [5]. Surgical resection, radiofrequency ablation, and liver transplantation remain the most effective curative therapies in selected patients. However, unlike other solid malignancies, the treatment of HCC must take multiple important factors into considerations. For example, the coexisting underlying liver diseases, such as chronic hepatitis B or C and alcoholic liver disease, had limited the extent and feasibility of liver resection. According to a recent analysis, only around 5–40% of non-cirrhotic HCC patients underwent liver resection, and this percentage was even much lower if the patients have chronic liver disease or overt cirrhosis [6].

Due to heterogeneous disease presentation and poor prognosis, many staging systems thus have been proposed to suggest appropriate treatment and predict survival outcome for patients with HCC. Among them, the American Joint Committee on Cancer (AJCC) Tumor/Node/Metastasis (TNM) staging system is one of the most commonly used staging systems to stratify the prognosis of patients with HCC [7, 8]. The latest edition, 8th edition, was released in December 2016 to further optimize the prognostic capability of the 7th edition [9, 10]. Major vascular invasion, for example, has been upgraded from T3b to T4 in this version. Despite important modifications, however, the newest edition has not stratified the tumors beyond 2 cm based on size. The staging and prognosis of either solitary small or large HCC without vascular invasion, based on this system, are essentially the same. Nevertheless, there were many other studies demonstrating that tumor diameter, in addition to vascular invasion, was also an important prognostic factor for HCC [11‐14]. Another recent study even showed that there was an apparent survival difference among stage I HCC patients with different tumor sizes [15]. Patients with larger HCC had significantly higher risks of tumor recurrence and death than those with smaller tumors after liver resection [15]. As a result, it is of urgent needs to reassess the impact of tumor diameter on the outcome of HCC and to enhance the staging system. The current study, by utilizing the data from the Chang Gung Research Database (CGRD), aimed to find out the optimal cutoff for tumor size to further stratify the 8^th edition of AJCC TNM staging system [15‐18]. To eliminate the potential bias due to different stages and treatment approaches, we examined patients with pathologically proven T1N0M0 HCC who underwent curative intent liver resection.

According to the 8th edition of AJCC TNM staging system for HCC, solitary small tumor (< 5 cm) without vascular invasion and solitary huge tumor (> 10 cm) without vascular invasion were all categorized as T1 lesions [9, 10]. As a result, the treatment recommendation and prognosis were deemed to be similar between these two entities. Nevertheless, our recent study demonstrated that in stage I HCC after liver resection, tumors larger than 10 cm had significantly higher risks of tumor recurrence and death than those smaller than 10 cm [15]. Single HCC > 5 cm without vascular invasion, in another study, was found to have a survival rate inferior to that of HCC < 5 cm [12]. There was even another report suggesting that single HCC should be assigned into three different groups according to the tumor size (≤ 5 cm, > 5 and ≤ 8 cm, and > 8 cm, respectively) [13]. Patients with larger HCC, as a result, did not have survival outcome comparable to those with smaller tumors as expected. A recent study further proposed that, due to their similar survivals, the T1b lesions should be integrated with T2 lesions to obtain a modified TNM staging [11]. These studies all indicated that tumor size did significantly impact the outcome of solitary HCC and should be considered in the conventional staging systems. In other words, there should be a subclassification within T1 stage to precisely predict patient outcome. The exact cutoff values, however, are still controversial among different literatures. The current study, by examining one of the largest and most comprehensive clinical databases worldwide, discovered that solitary HCC > 6.5 cm without vascular invasion had a DFS and liver specific-OS similar to those of T2 tumors. Hence, we proposed that T1 HCC can be further classified to accommodate a T1c subcategory: solitary tumor > 6.5 cm without vascular invasion. To further corroborate our findings, we performed Cox regression multivariate analysis and found that tumor size > 6.5 cm was one of the independent prognostic factors for tumor recurrence and liver-specific mortality after liver resection for T1 HCC. By conducting sensitivity tests consisting of different models, we again demonstrated that tumor size did influence the outcome of T1 HCC. All statistics in the sensitivity tests showed the same trend that patients with HCC larger than 6.5 cm had higher risks of recurrence and liver-specific death. This cutoff, coincidentally, corresponded to the criteria suggested by the University of California San Francisco (UCSF) that a solitary HCC larger than 6.5 cm without vascular invasion had significantly worse survivals after orthotopic liver transplantation [22, 23]. Therefore, we believe tumor size > 6.5 cm is an important prognostic factor in T1 HCC and should be considered in the TNM staging system.

Unlike a previous study which claimed that tumor size was not a prominent prognostic indicator in nonvascular invading solitary HCC receiving liver resection, the current study discovered that tumor size > 6.5 cm was indeed a significant prognostic factor among T1 HCC patients undergoing surgery [24]. The inconsistent results may be explained by the different study designs. In the current study, we incrementally divided T1b tumors into two groups and tried to find out a cutoff which could differentiate the new subcategory from the remaining T1 tumors. The resulting T1c subgroup had a survival, not only significantly shorter than the T1a/b tumors, but similarly poor with the T2 tumors. In contrast, the study conducted by Yang et al. divided patients into three groups (≤ 30 mm, 31‐50 mm, and > 50 mm) based on tumor size limitations between radiofrequency ablation and liver transplantation [24]. They compared the survival outcome of larger tumors (31‐50 mm or > 50 mm) against those of smaller ones (≤ 30 mm). The different cutoffs and analyses may lead to different conclusions. The disparate AJCC versions also rendered these results incomparable. The current study, by adopting the newest 8th edition of AJCC TNM staging system for HCC, is readily available to be applied in the real world clinical practice. Due to inferior survival outcome, the treatment strategy and surveillance protocol should be modified for this subgroup of patients. Adjuvant treatment with either transarterial chemoembolization (TACE) or systemic therapy (tyrosine kinase inhibitors or immune checkpoint inhibitors) could be considered for this subset of patients. Further prospective clinical trials are warranted to establish a more effective treatment protocol for these patients.

In addition to worse survivals, the current study also discovered that T1 HCC > 6.5 cm had less HCV infection and cirrhosis. There were more patients diagnosed at a younger age, too. Since younger HCC patients have been demonstrated to have lower rates of HCV infection and cirrhosis, it may explain the demographic disparities observed [25]. However, it is also likely that the carcinogenesis of T1c HCC is different from that of T1a/b tumors. The non-viral cause, such as fatty liver diseases, might have contributory roles in the pathogenesis of these large tumors. This speculation can be supported by our finding that non-viral cause accounted for more than 54% of T1c HCC in the present study, as compared to only 30% of T1a/b tumors (p < 0.001). Further studies are warranted to explore the causal relationships between these associations.

Despite remarkable findings, the current study still has several limitations. First, the current study was generated from the hospital-based database and cancer registry, more descriptive features, such as performance status, postoperative complications, and pathologic details; for example, hepatitis activity index, margin status, and histological grade, were inaccessible. The analysis of these variables was thus lacking. Second, since some T2 lesions, for example, bilobar tumors or more than 3 tumors, may not undergo surgery, the surgical survivals obtained herein may not fully represent the outcome associated with all T2 lesions. This was why we did not propose to upgrade our new “T1c” subcategory into T2 stage (Supplementary Fig. S3). We only intended to find out an optimal size cutoff within the T1 stage to differentiate those patients at risk. As a result, further studies are warranted to examine whether T1c stage should be integrated into T2 stage. Third, as mentioned above, the current study failed to suggest adequate treatment strategy for T1c lesions. Further well-designed prospective studies targeting at this subset of patients are thus necessary to establish appropriate treatment guidelines. Next, although the potential recall bias could be avoided by prospectively registering the daily clinical data into the CGRD, referral bias was in the meanwhile inevitable, since the CGMHs are the largest tertiary care center in Taiwan [26, 27]. Last but not the least, since the present study was based primarily on data from a single country, the patient population as a result would be rather uniform. The lack of an external validation cohort consisted of different ethnic groups, therefore, would be another drawback of the current study. It would be more convincing if the data can be confirmed by HCC data sets from countries with a more diverse population. Further studies incorporating external validation cohorts are necessary to approve our findings.

Our CGRD-based study demonstrated that tumor size would significantly impact the survival outcome of T1 HCC after surgery. Solitary tumor > 6.5 cm without vascular invasion, after serial analysis, was found to have a survival similar to that of T2 HCC. As a result, we proposed a subclassification within T1 HCC, T1c: solitary tumor > 6.5 cm without vascular invasion, to further stratify those patients at risk. Due to significantly higher risks of recurrence and death, adjuvant treatment should be considered for this subset of T1 HCC. Further studies are mandatory to validate our findings.