In this study, we found that several newly recognized patterns of HCC recurrence or progression after RFA occurred frequently in patients with periportal HCC compared with those patients with nonperiportal HCC, such as rapid intrahepatic or extrahepatic progression and rapid portal vein tumor thrombosis, even the local complete ablation was achieved after the initial treatment. And these patterns of HCC recurrence or progression was strongly associated with periportal HCC, and indicated poor prognosis. More importantly, we also demonstrated that patients with single periportal HCC had worse local tumor control and survival than patients with single nonperiportal HCC in the treatment of RFA as the first-line therapy. This study therefore raises an important question about exploring the optimal ablation modality for single periportal HCC in the future studies.

In terms of the technique of sufficient ablation, a safe ablation margin of 3 mm or more has been recognized as essential for preventing local tumor recurrence [15, 16]. However, it is practically difficult for periportal HCC to successfully create a safe ablative margin in the direction of the margin of HCC adjacent to the portal vein. In this study, periportal HCC after RFA exhibited a higher LTP rate than nonperiportal HCC. This was attributed to factors related to the adverse effect of the portal vein on RFA. First, the safe ablation margin was limited by anatomical location and the “heat sink effect” caused by the portal vein. Second, the adverse effect of the portal vein may reduce thermal damage to cancer cells, leading to viable residual cancer cells regenerating again during the follow-up (Fig. 3). However, the results of Kang et al. suggested that the long-term therapeutic outcomes of RFA for small perivascular HCC were similar to those for nonperivascular HCC [13]. This controversy may be attributed to several reasons. First, “perivascular” in their study was referred to as “periportal” and “perivenous”, but we only referred to periportal HCC. Second, the tumor sizes of periportal HCC in our study were larger. In addition, technical factors could lead to differences in these results, such as ablation strategy, radiofrequency power settings and operator experience. A recent study suggested that periportal HCC was an independent risk factor for LTP but not perivenous HCC, although the cause was unclear [8], and they refined “periportal HCC” instead of “perivascular HCC”.

Fig. 3
figure3

Local tumor progression (LTP) after RFA for periportal HCC in a 57-year-old man. (A) Dynamic contrast-enhanced axial magnetic resonance (DCE-MRI) scan obtained showing a small HCC (arrow) in periportal location before RFA. (B) CT scan obtained during RFA showing a multitip expandable electrode adjacent to the portal vein (arrow). (C) CT scan obtained during portal venous phase 1 months after RFA showing the complete ablation zone (arrow) adjacent to the portal vein. (D) CT scan obtained during hepatic arterial phase and portal venous phase (not shown) 53 months after RFA showing the LTP, a small arterial enhancing nodule (arrows), with washout at portal venous phase. (E) CT scan obtained during portal venous phase 1 months after TACE+RFA showing the complete ablation zone (arrow) adjacent to the portal vein, “intratumoral lipiodol deposition” can be seen in the ablation zone. (F) CT scan obtained during portal venous phase 4 months after TACE+RFA showing the complete ablation zone (arrow) adjacent to the portal vein

To create a sufficient ablation zone for periportal HCC, portal vein injury seems to be inevitable due to puncture and thermal damage during RFA. However, the procedure of ablation for periportal HCC could increase the risk of rapid intrahepatic neoplastic progression, PVTT or extrahepatic spread through the injured portal system [9, 17]. Similar patterns of tumor recurrence associated with periportal HCCs have been reported in previous studies [10, 11, 18,19,20]. Among them, Kang et al. found that the rate of aggressive intrasegmental recurrence (AIR) was only 3.7% (20 of 539 patients) in all patients; however, the rate of AIR markedly increased to 15% (11 of 72 patients) in patients with periportal HCC [11]. Song et al. found that the rate of AIR was as low as 4.5% (1 of 22 patients) when TACE combined with RFA was used to treat periportal HCC [18]. In this study, three of 56 patients (5.4%) in the periportal group experienced IDR with aggressive progression after RFA (Fig. 4). Moreover, one patient (1.8%) with periportal HCC exhibited extrahepatic recurrence with rapid progression after RFA (Fig. 5); and another two patients (3.6%) with periportal HCC suffered RFA-related rapid PVTT within 7 months after RFA (Supplemental Fig. 2). All these patients showed complete ablation during the follow-up period, and there was no evidence of preablation extrahepatic metastasis or postablation intrahepatic recurrence. Among those new patterns of tumor recurrence or progression in this study, gasification in the ablation zone or even in portal vein during RFA was observed in most of those cases, which means increased intertumoral pressure during RFA due to the rapidly increased temperature. Therefore, gasification in the ablation zone or portal vein during RFA for periportal HCC may indicate a high risk of tumor recurrence or metastasis after ablation. Although the mechanism of those new patterns of recurrence is unknown, we suspect that rapid heating of periportal HCC during RFA and poorly differentiated HCC phenotype could play important roles in the process of tumor progression or recurrence after RFA; on the one hand, a suddenly increased intratumoral pressure due to rapid heating could promote viable tumor cells to spread directly into the peripheral liver or extrahepatic organs through the injured portal system [9, 11, 19]; On the other hand, poorly differentiated HCC phenotype may potentially increase the risk of tumor cells escape and distant metastasis during ablation [21, 22].

Fig. 4
figure4

IDR with aggressive progression after RFA for periportal HCC in a 65-year-old man. (A) CT scan obtained during RFA showing a periportal HCC mass treated with TACE, and gasification (green arrowhead) was observed in the ablation zone during RFA. (B-C) CT scan obtained during the portal venous phase 1 month after RFA showing the complete ablation zone (arrow) adjacent to the portal vein (green arrowhead). (D) CT scan obtained during the portal venous phase 3 months after RFA showing multiple newly occurring small HCCs of similar size (arrow) surrounding the complete ablation zone (*)

Fig. 5
figure5

Extrahepatic recurrence with rapid progression after TACE+RFA for periportal HCC in a 61-year-old man. (A-B) DCE-MRI: hepatic arterial phase (A) and DWI (B) showing a small HCC (arrow) in the periportal location before TACE+RFA. (C-D) CT scan obtained during the portal venous phase 3 months after TACE+RFA showing the complete ablation zone (arrow) adjacent to the portal vein (arrowhead). (E) DWI scan obtained 6 months after TACE+RFA shows bone metastasis (arrow). (F) CT scan obtained 6 months after TACE+RFA showing thoracic wall metastases and multiple lung metastases (arrow). (G-I) CT scan obtained during the portal venous phase 12 months after TACE+RFA showing the complete ablation zone (arrow) adjacent to the portal vein accompanied by thoracic wall and lung metastases

In addition, residual tumor cells after RFA for periportal HCC can accelerate portal vein invasion. In contrast to nonperiportal HCC, due to the shorter distance that the residual cancer surrounded the ablation zone from the portal vein and the lack of a normal liver tissue barrier between them, the residual tumor cells tended to accelerate the process of PVTT. In this study, residual tumors directly resulted in portal vein invasion in two patients (3.6%) after initial RFA (Fig. 6). We also found that a higher incidence of PVTT with a shorter median time was observed in patients with periportal HCC than patients with nonperiportal HCC.

Fig. 6
figure6

Residual tumor with rapid progression was observed in a 57-year-old man with periportal HCC, which showed direct invasion of the portal vein by residual tumor after RFA. (A) Dynamic contrast-enhanced axial magnetic resonance (DCE-MRI) scan obtained showing a small HCC (arrow) directly connected to the portal vein (arrowhead). (B) CT scan obtained during the portal venous phase 4 months after RFA showing the insufficient ablation margin (arrow) connected to the portal vein (arrowhead). (C)-(D) CT scan obtained during the hepatic arterial phase and portal venous phase 9 months after RFA showing local tumor progression accompanied by portal vein invasion (arrowhead)

In this study, we identified three adverse risk factors (periportal, tumor size, and AFP ≥ 400 ng/ml) that predict tumor progression after RFA in the univariate and multivariate analysis. Interestingly, we also found that patients with single periportal HCC of 3-5 cm in diameter tended to have worse prognosis but similar local tumor control than those patients in the subgroup of nonperiportal HCC. This may be attributed to that tumor size is the most important factor of LTP, while “periportal” is one of the most important risk factors tumor progression and impairs long-term survival. In any case, particular caution must be taken in the treatment of periportal HCC with larger tumor size or AFP ≥ 400 ng/ml for ablation. However, there are no available guidelines for ablation for periportal HCC, and we have not been able to draw any conclusion about the efficacy of RFA using a multitip expandable electrode in the treatment of periportal HCC due to lack of sufficient evidence. Recently, a retrospective study with a small sample suggested that microwave ablation provides better local tumor control over RFA as a first-line therapeutic option for small single periportal HCC [23]. Further prospective controlled studies are urgently necessary to determine which ablation option among RFA, microwave ablation, cryoablation, and other ablation is best option for periportal HCC.

To reduce the potential risk of tumor spread during ablation, we recommend several ablation strategies in the treatment of periportal HCC for ablation based on our experiences, such as using a mono-tip electrode needle, managing longer ablation times at lower power to minimize gasification during ablation [11, 20], and combining RFA with TACE [18, 24]. Immediate imaging assessment after ablation and closer follow-up monitoring are necessary for patients with periportal HCC to prevent rapid tumor progression due to residual tumor or tumor recurrence. In addition, non-RFA-related technologies could provide an alternative option for periportal HCC to prevent or minimize newly recognized RFA-related tumor recurrence [20], such as microwave ablation [25], cryoablation [26] and irreversible electroporation [27], and iodine-125 seed implantation [28].

Our study has some limitations. First, this was a retrospective study with a small sample size based on medical records. Second, the exact cause of the new RFA-related tumor recurrence of periportal HCC lacked histopathological evidence, although the recurrence patterns did not occur in nonperiportal HCC. Third, data regarding the time interval between TACE and RFA were not evaluated. Finally, there was no uniform posttreatment or surveillance schedule.

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