In the present study, tumor markers, size, and number reflecting the BCLC stage were risk factors for early recurrence after curative hepatectomy for initial HCC. A longer operative time and macrovascular PVTT also affected early recurrence. Furthermore, the early recurrence group exhibited poor OS after both the surgery and the time of recurrence. Furthermore, multiple tumor recurrences were associated with a lower PNI, larger tumor size, moderately differentiated tumors, and macrovascular PVTT. Patients with multiple recurrent nodules had a poorer OS and shorter time to recurrence, especially those with ≥ three nodules and distant metastases.
Biological tumor properties, including tumor markers (AFP and DCP), tumor size, multiple nodules, and microvascular PVTT, were risk factors for early recurrence after hepatectomy for HCC. BCLC stage was an independent risk factor in the multivariate analysis because this staging system was reflected by tumor size, number of tumors, and PVTT. Previous studies recognized these factors as risk factors for early recurrence11–14. Tumor cells may already be present in the remnant liver or bloodstream of patients with potential malignant tumors before hepatectomy, as described above. In the present study, operative time was another factor that affected early recurrence. A previous study reported that among surgical factors, greater amounts of blood loss and longer operative time were found to be risk factors for early recurrence.15 Another study showed that portal vein clamp during hepatectomy induce early HCC recurrence owing to liver ischemic-reperfusion injury (IRI).16 A longer operative time may cause IRI through repeated Pringle maneuvers, thus inducing early recurrence.
Notably, early recurrence was associated with multiple nodular recurrences and distant metastases in the present study. However, the relationship between the recurrence period and patterns has not been well discussed in previous reports. There are two possible types of multifocal HCC recurrence after resection. One is multiple HCCs of the MO, and the other is IM arising from a primary HCC. IM is generally considered to arise within 2 years postoperatively, whereas MO is considered to arise > 2 years postoperatively.17 Based on these findings, most early recurrent HCCs in the present study might have been IM and tend to arise as multiple nodules or distant metastases, although we did not obtain any molecular evidence of IM or MO.
The early recurrence group had significantly lower OS than the late recurrence group, even after the time of recurrence. Furthermore, several previous studies have reported poorer survival in patients with early HCC recurrence.12, 13 This may be related to the higher rate of multiple recurrences or distant metastases associated with IM. In such cases, it is possible that occult cancer cells that were undetected in imaging studies already existed at the time of surgery. In the present study, the BCLC stage was the only independent risk factor for early recurrence. Therefore, careful surveys are needed after surgery to detect early recurrence, especially in BCLC stage B and C patients, and to initiate appropriate treatment immediately.
Regarding the analysis of the recurrence patterns, tumor diameter and PNI were risk factors for multiple nodular recurrences among the preoperatively detectable patient factors. A previous study revealed AFP levels, tumor size, tumor necrosis, and intraoperative blood loss as risk factors for multiple recurrences.18 However, no studies have assessed the number of recurrent nodules or immunonutritional/inflammatory indices. We previously reported that patients with low PNI had lower OS and progression-free survival after hepatectomy for HCC and that PNI was an independent prognostic factor for OS.19 Patients with a low PNI may have higher carcinogenesis, resulting in multiple nodular recurrences. Histological findings also showed a high malignant potential, a lower degree of tumor differentiation, and a higher incidence of microvascular and macrovascular PVTT in the multiple nodular recurrence group. A previous study also showed that disseminated HCC recurrence, defined as the presence of > 10 nodules in the bilateral lobes and a total tumor size of > 10 cm within 3 months after hepatectomy, was associated with a higher incidence of poor tumor grade and PVTT.12 Regarding the underlying liver disease, the incidence of liver cirrhosis was significantly lower in the multiple nodular recurrence group. Notably, most single recurrences were considered MO arising in the fibrotic liver, whereas multiple recurrences were considered IM regardless of the underlying liver disease. A previous study that compared postoperative recurrence between MO and IM groups showed that liver cirrhosis was highly associated with MO recurrence.20 They classified recurrence as MO or IM based on histological findings. However, we could not histologically evaluate the origin of the recurrence or recurrence patterns in the present study.
In the survival analysis, the multiple recurrence group had a significantly lower OS than the single recurrence group when the comparison was according to the time of operation, whereas there was no difference when the comparison was based on the time of recurrence. In a more detailed analysis, the group with ≥ three recurrent tumor nodules exhibited significantly poorer survival, even after the time of recurrence, whereas the groups with single and two nodules showed similar survival. The optimal cutoff value for the number of recurrent tumors was suspected to be three in predicting prognosis after recurrence. In a previous study, patients with ≥ three recurrent nodules exhibited significantly lower OS after resection than those with ≤ two nodules, whereas there were no differences between those with single and two recurrent nodules or those with three and ≥ four recurrent nodules.21 Another study showed lower OS in patients with ≥ four recurrent nodules than in those with ≤ three nodules.18 In the present study, the time to recurrence after surgery was significantly shorter in the multiple recurrence group, especially in patients with ≥ three nodules or distant metastases, than in the single recurrence group. Based on these findings, intrahepatic recurrence with ≥ three nodules may be IM rather than MO. A previous study that compared postoperative recurrence between MO and IM groups showed that the IM group had a significantly higher incidence of multiple nodular recurrences and a much shorter median interval for recurrence after the initial hepatectomy.20 These results are consistent with the finding that the early recurrence group had a significantly higher incidence of ≥ three nodules and distant metastases.
Systemic therapies using molecular-targeted agents (MATs) and immune checkpoint inhibitors (ICIs) have been developed to treat HCC. However, the efficacy of adjuvant chemotherapy remains controversial. A randomized controlled trial (RCT) that investigated the efficacy of sorafenib as adjuvant therapy for patients with HCC after hepatectomy or local ablation showed no significant treatment effect of sorafenib on recurrence-free survival, time to recurrence, or OS.21 There is currently no evidence for the benefit of ICIs as adjuvant therapy for HCC; however, several clinical trials using ICIs as adjuvant therapy are ongoing. Among studies on adoptive immunotherapy, such as lymphokine-activated, cytokine-induced, and natural killer cells, a meta-analysis of RCTs showed that adoptive immunotherapy can significantly improve OS and recurrence-free survival after curative treatment in the early stage (< 3 years) but not in the late stage (5 years).22 This result indicates that adjuvant immunotherapy may eliminate small IM but not affect liver cirrhosis or prevent multicentric recurrence in the remnant liver. If adjuvant treatment is administered to groups at a high risk of IM, it may prevent recurrence and prolong survival. Preoperative prediction of the recurrence patterns of IM and MO is considered important in selecting high-risk groups. As an alternative method, assessing recurrence time and patterns may help us judge the high-risk population to be treated systemically.
In conclusion, advanced-stage HCC is associated with an increased risk of early recurrence and multiple or distant tumor recurrences after curative hepatectomy. Multiple tumor recurrences with ≥ three nodules tended to occur earlier postoperatively than single nodular recurrences. Patients with early recurrence and multiple or distant tumor recurrences should be carefully followed up because they exhibit poor survival after initial recurrence, considering the possibility of IM rather than MO.