Introduction: Recurrence after microwave ablation (MWA) has not been extensively studied. We aimed to investigate the patterns, treatments, and survival of patients with hepatocellular carcinoma (HCC) who experienced early and late recurrence after MWA. Methods: This retrospective study included patients with HCC recurrence after MWA as the initial treatment from January 2008 to December 2021. Recurrence patterns, treatments, and outcomes between patients with early and late HCC recurrence were compared. Prognostic factors of post-recurrence survival (PRS) were identified by multivariable Cox regression analyses. Results: Among 222 patients, 128 developed early recurrence (≤2 years after MWA) and 94 had late recurrence (>2 years). Majority of the recurrent HCC were intrahepatic-only recurrence, within the Milan criteria, and received potentially curative treatment. No significant differences in the recurrence patterns, vascular invasion, tumor staging, post-recurrence treatments, or median PRS (35.0 vs. 33.0 months, p = 0.523) were identified between patients with early and late recurrence. Multivariable analyses suggested that multiple tumor number (hazard ratio [HR]: 1.54; 95% CI: 1.03–2.30, p = 0.038), extrahepatic recurrence (HR: 2.14, 95% CI: 1.16–3.92, p = 0.015), vascular invasion (HR: 2.37, 95% CI: 1.18–4.76, p = 0.038), and higher ALBI grade (HR: 2.18, 95% CI: 1.54–3.08, p < 0.001) were independent risk factors of worse PRS, while curative treatment after recurrence (HR: 0.59, 95% CI: 0.38–0.92, p = 0.020) was associated with better PRS. Conclusions: No differences in recurrence patterns, post-recurrence treatments, or PRS were found between HCC patients with early and late recurrence following MWA. Tumor burden and patients’ liver function reserve should be considered to decide the optimal post-recurrence treatment after MWA.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death with 5-year survival of 20–40% [1]. For patients with Barcelona clinic liver cancer (BCLC) stage 0 or A HCC, local ablation, surgery resection (SR), and liver transplantation are recommended treatments [2, 3]. Studies suggested that survival rate was comparable between SR and microwave ablation (MWA) for HCC within the Milan criteria [4‒6]. MWA is currently used as the first-line treatment for some patients with HCC [7, 8]. Although both local ablation and SR were considered as the curative treatments for early-staged HCC, the 5-year recurrence rate could be up to 70–80%, and the cumulative 5-year overall survival (OS) rate could be as low as 36.8% [9, 10].

HCC recurrence can be defined as early and late recurrence [11]. Early recurrence (≤2 years) is thought to be caused by intrahepatic metastasis from the primary tumor and is commonly associated with the biological characteristics of the original tumor. In contrast, late recurrence (>2 years) is frequently caused by a de novo tumor due to multi-centric tumorigenesis and is usually associated with underlying liver conditions like cirrhosis and active hepatitis [12, 13]. For HCC patients, time to recurrence was found to be a significant risk factor for OS after curative treatment, and patients with early recurrence had poorer prognosis than those with late recurrence [13, 14]. Some studies suggested that patients with late recurrence had better post-recurrence survival (PRS) than those with early recurrence [13‒16]. However, majority of the studies are HCC patients who received SR. A few studies reported the recurrence patterns of HCC after radiofrequency ablation [12, 16]. Recurrence after MWA has not been extensively studied. Therefore, we conducted a retrospective study to investigate the recurrence patterns, treatments, and the prognostic factors associated with PRS in patients with early and late recurrence after MWA.

Patient Cohort

This retrospective study was approved by the XiJing Hospital of Digestive Diseases and conducted according to the ethical guidelines of the 1975 Declaration of Helsinki. The need for a written informed consent was waived by the XiJing Hospital of Digestive Diseases. Patients who were ineligible for surgery or refused surgical treatment underwent ultrasound (US)-guided percutaneous MWA treatment for HCC. HCC patients who received MWA as initial treatment and had HCC recurrence during January 2008 to December 2021 were included. HCC and HCC recurrence were diagnosed by histology or noninvasive methods according to the guidelines of European Association for the Study of Liver (EASL) [3]. The inclusion criteria were as follows: (1) initial HCC was within the Milan criteria (solitary tumors ≤5 cm or up to three tumors ≤3 cm); (2) MWA was used as the initial treatment; (3) HCC recurrence was confirmed after initial MWA. The exclusion criteria were as follows: (1) comorbidity with other malignancies; (2) loss of follow-up within 6 months after initial MWA; (3) recurrence within 1 month after initial MWA; (4) missing data on essential prognostic variables. The data were censored on September 30, 2022.

Follow-Up Surveillance and Data Collection

One month after MWA treatment, all patients underwent contrast-enhanced CT or MRI to evaluate the technical success rate. After the initial CT/MRI scan, patients were subsequently followed up every 3–6 months until death or loss of follow-up. Each follow-up visit included a physical examination, liver function, α-fetoprotein (AFP), and at least one imaging examination (abdominal US or contrast-enhanced CT or MRI). Patients with elevated AFP or suspicious lesions on US screening had contrast-enhanced CT or MRI to confirm tumor recurrence. If the imaging findings were uncertain, a biopsy of the nodules was performed. Patients who did not visit our hospital as scheduled were telephoned to obtain the recurrence information, treatment modalities, and living status.

Clinical and demographic data were retrieved from the medical records, including sex, age, maximum tumor size, number of tumors, tumor location, etiology, antiviral therapy, cirrhosis, Child-Turcotte-Pugh grade, albumin-bilirubin (ALBI) grade, serum AFP, BCLC staging, performance status, portal hypertension, serum albumin, aspartic transaminase, alanine aminotransferase, total bilirubin, international normalized ratio (INR), platelet counts, neutrophil-lymphocyte ratio (NLR), and aspartate aminotransferase‐to‐platelet ratio index (APRI). OS was calculated from the date of initial MWA to either the date of death or the last follow-up. PRS was calculated from the date of diagnosis of initial recurrence to the date of death or the last follow-up. Curative treatment options for relapsed HCC included SR, local ablation, and liver transplantation, while non-curative treatment included transcatheter arterial chemoembolization, targeted therapies (such as sorafenib), and supportive treatment.

Statistical Analysis

Categorical variables were expressed as counts and percentages and compared using Pearson’s χ2 test or Fisher’s exact test. Continuous variables were presented in medians with interquartile range and compared by Mann-Whitney U test. PRS curves were generated using the Kaplan-Meier method and compared with the log-rank test. Uni- and multivariable Cox proportional hazard regression analyses were performed to identify the predictors associated with PRS.

All statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA) and R version 4.1.3 software (R Foundation for Statistical Computing). A two-tailed p value <0.05 was considered as statistically significant.

Characteristics of the Patients with HCC Recurrence

A total of 222 patients were finally included with a median follow-up time of 87.0 months. Among them, 128 (57.7%) patients experienced early recurrence and 94 (42.3%) had late recurrence (Fig. 1). The baseline characteristics of the patients before MWA are shown in Table 1. No significant differences were observed between patients with early and late recurrence in sex, age, etiology, liver functions, performance status, initial tumor status, and ALBI grade. Patients with early HCC recurrence had significantly higher NLR than those with late recurrence (p = 0.025).

Fig. 1.

Flowchart of the patient selection in this study. HCC, hepatocellular carcinoma; MWA, microwave ablation; PRS, post-recurrence survival.

Fig. 1.

Flowchart of the patient selection in this study. HCC, hepatocellular carcinoma; MWA, microwave ablation; PRS, post-recurrence survival.

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Table 1.

Characteristics of the study population before MWA

VariablesTotal recurrence (n = 222), n (%)Early recurrence (n = 128), n (%)Late recurrence (n = 94), n (%)p value
Age >60 years 78 (35.1) 43 (33.6) 35 (37.2) 0.575 
Male 176 (79.3) 105 (82.0) 71 (75.5) 0.238 
Etiology    0.466 
 HBV 182 (82.0) 107 (83.6) 75 (79.8)  
 Non-HBV 40 (18.0) 21 (16.4) 19 (20.2)  
Child-Pugh grade    0.814 
 A 195 (87.8) 113 (88.3) 82 (87.2)  
 B 27 (12.2) 15 (11.7) 12 (12.8)  
AFP    0.199 
 ≤400 ng/mL 185 (83.3) 102 (79.7) 83 (88.3)  
 >400 ng/mL 37 (16.7) 26 (20.3) 11 (11.7)  
NLR 1.9 (1.3, 2.8) 2.1 (1.5, 2.7) 1.7 (1.2, 2.6) 0.025 
Tumor size    0.396 
 ≤3 cm 196 (88.3) 111 (86.7) 85 (90.4)  
 3.1–5 cm 26 (11.7) 17 (13.3) 9 (9.6)  
Tumor number    0.953 
 Solitary 194 (87.4) 112 (87.5) 82 (87.2)  
 Multiple 28 (12.6) 16 (12.5) 12 (12.8)  
Adjacent to organs/vessels    0.299 
 Yes 40 (18.0) 26 (20.3) 14 (14.9)  
 No 182 (82.0) 102 (79.7) 80 (85.1)  
Liver cirrhosis 194 (87.4) 114 (89.1) 80 (85.1) 0.380 
Portal hypertension 152 (68.5) 85 (66.4) 67 (71.3) 0.440 
BCLC staging    0.795 
 0 67 (30.2) 38 (29.7) 29 (30.9)  
 A 125 (56.3) 71 (55.5) 54 (57.4)  
 B 30 (13.5) 19 (14.8) 11 (11.7)  
Performance status score    0.159 
 0 184 (82.9) 110 (85.9) 74 (78.7)  
 1 38 (17.1) 18 (14.1) 20 (21.3)  
APRI 1.1 (0.6, 1.9) 1.0 (0.5, 1.8) 1.1 (0.7, 2.1) 0.082 
Elevated serum ALT 64 (28.8) 37 (28.9) 27 (28.7) 0.976 
Elevated serum AST 67 (30.2) 39 (30.5) 28 (29.8) 0.913 
Elevated serum INR 48 (21.6) 26 (20.3) 22 (23.4) 0.580 
TBIL>34.1 μmol/L 26 (11.7) 12 (9.4) 14 (14.9) 0.206 
ALB <40 g/L 128 (57.7) 67 (54.5) 61 (61.6) 0.284 
ALBI grade    0.369 
 Grade 1 107 (48.2) 65 (50.8) 42 (44.7)  
 Grade 2, 3 115 (51.8) 63 (49.2) 52 (55.3)  
Follow-up schedule    0.736 
 3-monthly surveillance 101 (45.4) 57 (44.5) 44 (46.8)  
 6-monthly surveillance 121 (54.5) 71 (55.5) 50 (53.2)  
Follow-up duration 87.0 (56.0, 125.0) 85.0 (52.0, 123.0) 101.0 (69.0, 125.0) 0.066 
VariablesTotal recurrence (n = 222), n (%)Early recurrence (n = 128), n (%)Late recurrence (n = 94), n (%)p value
Age >60 years 78 (35.1) 43 (33.6) 35 (37.2) 0.575 
Male 176 (79.3) 105 (82.0) 71 (75.5) 0.238 
Etiology    0.466 
 HBV 182 (82.0) 107 (83.6) 75 (79.8)  
 Non-HBV 40 (18.0) 21 (16.4) 19 (20.2)  
Child-Pugh grade    0.814 
 A 195 (87.8) 113 (88.3) 82 (87.2)  
 B 27 (12.2) 15 (11.7) 12 (12.8)  
AFP    0.199 
 ≤400 ng/mL 185 (83.3) 102 (79.7) 83 (88.3)  
 >400 ng/mL 37 (16.7) 26 (20.3) 11 (11.7)  
NLR 1.9 (1.3, 2.8) 2.1 (1.5, 2.7) 1.7 (1.2, 2.6) 0.025 
Tumor size    0.396 
 ≤3 cm 196 (88.3) 111 (86.7) 85 (90.4)  
 3.1–5 cm 26 (11.7) 17 (13.3) 9 (9.6)  
Tumor number    0.953 
 Solitary 194 (87.4) 112 (87.5) 82 (87.2)  
 Multiple 28 (12.6) 16 (12.5) 12 (12.8)  
Adjacent to organs/vessels    0.299 
 Yes 40 (18.0) 26 (20.3) 14 (14.9)  
 No 182 (82.0) 102 (79.7) 80 (85.1)  
Liver cirrhosis 194 (87.4) 114 (89.1) 80 (85.1) 0.380 
Portal hypertension 152 (68.5) 85 (66.4) 67 (71.3) 0.440 
BCLC staging    0.795 
 0 67 (30.2) 38 (29.7) 29 (30.9)  
 A 125 (56.3) 71 (55.5) 54 (57.4)  
 B 30 (13.5) 19 (14.8) 11 (11.7)  
Performance status score    0.159 
 0 184 (82.9) 110 (85.9) 74 (78.7)  
 1 38 (17.1) 18 (14.1) 20 (21.3)  
APRI 1.1 (0.6, 1.9) 1.0 (0.5, 1.8) 1.1 (0.7, 2.1) 0.082 
Elevated serum ALT 64 (28.8) 37 (28.9) 27 (28.7) 0.976 
Elevated serum AST 67 (30.2) 39 (30.5) 28 (29.8) 0.913 
Elevated serum INR 48 (21.6) 26 (20.3) 22 (23.4) 0.580 
TBIL>34.1 μmol/L 26 (11.7) 12 (9.4) 14 (14.9) 0.206 
ALB <40 g/L 128 (57.7) 67 (54.5) 61 (61.6) 0.284 
ALBI grade    0.369 
 Grade 1 107 (48.2) 65 (50.8) 42 (44.7)  
 Grade 2, 3 115 (51.8) 63 (49.2) 52 (55.3)  
Follow-up schedule    0.736 
 3-monthly surveillance 101 (45.4) 57 (44.5) 44 (46.8)  
 6-monthly surveillance 121 (54.5) 71 (55.5) 50 (53.2)  
Follow-up duration 87.0 (56.0, 125.0) 85.0 (52.0, 123.0) 101.0 (69.0, 125.0) 0.066 

The bold p values represent the significance between the two groups.

NLR, neutrophil-lymphocyte ratio; HBV, hepatitis B virus; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBIL, total bilirubin level; INR, international normalized ratio; ALB, albumin; ALBI, albumin-bilirubin, AFP, α-fetoprotein; BCLC, Barcelona clinic liver cancer; MWA, microwave ablation; APRI, aspartate aminotransferase‐to‐platelet ratio index.

Recurrence Patterns, Post-Recurrence Treatments, and Outcomes

For recurrence patterns, the majority of the recurrent tumors were intrahepatic-only (86.5%, 192/222) recurrence, within the Milan criteria (74.8%, 166/222), and were candidates for potentially curative treatment (75.7%, 168/222). No significant differences were observed between patients with early and late recurrence (Table 2). As shown in Table 2, patients who developed early recurrence after MWA had significantly shorter median OS than those with late recurrence (49.0 vs. 84.0 months, p < 0.001), while PRS was comparable (35.0 vs. 33.0 months, p = 0.523) in the two groups.

Table 2.

Recurrence patterns, treatment modalities, and outcomes

Outcomes and treatment modalitiesOverall recurrence (n = 222), n (%)Early recurrence (n = 128), n (%)Late recurrence (n = 94), n (%)p value
Patterns of initial recurrence    0.418 
 Intrahepatic-only 192 (86.5) 110 (85.9) 82 (87.2)  
 Extrahepatic-only 9 (4.0) 7 (5.5) 2 (2.2)  
 Intrahepatic and extrahepatic 21 (9.5) 11 (8.6) 10 (10.6)  
Extent of initial recurrence    0.474 
 Within Milan criteria 166 (74.8) 98 (76.6) 68 (72.3)  
 Beyond Milan criteria 56 (25.2) 30 (23.4) 26 (27.7)  
Tumor number at initial recurrence    0.420 
 Single 159 (71.6) 89 (65.5) 70 (74.5)  
 Multiple 63 (28.4) 39 (30.5) 24 (25.5)  
Vascular invasion at recurrence    0.242 
 No 206 (92.8) 121 (94.5) 85 (90.4)  
 Yes 16 (7.2) 7 (5.5) 9 (9.6)  
Treatment modalities for initial recurrence    0.321 
 Potentially curative treatment 168 (75.7) 100 (78.1) 68 (72.3)  
 Non-curative treatment 54 (24.3) 28 (21.9) 26 (27.7)  
  TACE 23 (10.4) 9 (7.0) 14 (14.9)  
  Targeted therapy 17 (7.7) 13 (10.2) 4 (4.3)  
  Supportive care 14 (6.3) 6 (4.7) 8 (8.5)  
Median OS from MWA (95% CI), months 65.0 (59.1–70.9) 49.0 (40.1–57.9) 84.0 (71.8–96.2) <0.001 
 1-year OS rate 99.5 99.2 100.0  
 3-year OS rate 78.6 69.8 90.3  
 5-year OS rate 55.7 41.9 67.8  
 10-year OS rate 18.6 16.7 21.9  
Median PRS from initial recurrence (95% CI), months 33.0 (27.2–38.8) 35.0 (27.2–42.8) 33.0 (24.1–41.9) 0.523 
 1-year PRS rate 83.4 85.8 82.3  
 3-year PRS rate 47.9 48.5 47.0  
 5-year PRS rate 28.2 26.3 32.0  
Outcomes and treatment modalitiesOverall recurrence (n = 222), n (%)Early recurrence (n = 128), n (%)Late recurrence (n = 94), n (%)p value
Patterns of initial recurrence    0.418 
 Intrahepatic-only 192 (86.5) 110 (85.9) 82 (87.2)  
 Extrahepatic-only 9 (4.0) 7 (5.5) 2 (2.2)  
 Intrahepatic and extrahepatic 21 (9.5) 11 (8.6) 10 (10.6)  
Extent of initial recurrence    0.474 
 Within Milan criteria 166 (74.8) 98 (76.6) 68 (72.3)  
 Beyond Milan criteria 56 (25.2) 30 (23.4) 26 (27.7)  
Tumor number at initial recurrence    0.420 
 Single 159 (71.6) 89 (65.5) 70 (74.5)  
 Multiple 63 (28.4) 39 (30.5) 24 (25.5)  
Vascular invasion at recurrence    0.242 
 No 206 (92.8) 121 (94.5) 85 (90.4)  
 Yes 16 (7.2) 7 (5.5) 9 (9.6)  
Treatment modalities for initial recurrence    0.321 
 Potentially curative treatment 168 (75.7) 100 (78.1) 68 (72.3)  
 Non-curative treatment 54 (24.3) 28 (21.9) 26 (27.7)  
  TACE 23 (10.4) 9 (7.0) 14 (14.9)  
  Targeted therapy 17 (7.7) 13 (10.2) 4 (4.3)  
  Supportive care 14 (6.3) 6 (4.7) 8 (8.5)  
Median OS from MWA (95% CI), months 65.0 (59.1–70.9) 49.0 (40.1–57.9) 84.0 (71.8–96.2) <0.001 
 1-year OS rate 99.5 99.2 100.0  
 3-year OS rate 78.6 69.8 90.3  
 5-year OS rate 55.7 41.9 67.8  
 10-year OS rate 18.6 16.7 21.9  
Median PRS from initial recurrence (95% CI), months 33.0 (27.2–38.8) 35.0 (27.2–42.8) 33.0 (24.1–41.9) 0.523 
 1-year PRS rate 83.4 85.8 82.3  
 3-year PRS rate 47.9 48.5 47.0  
 5-year PRS rate 28.2 26.3 32.0  

The bold p values represent the significance between the two groups.

OS, overall survival; PRS, post-recurrence survival; TACE, transcatheter arterial chemoembolization; MWA, microwave ablation.

Prognostic Factors for PRS after MWA

Multivariable Cox regression analyses suggested that multiple recurrent tumors (hazard ratio [HR]: 1.54; 95% CI: 1.03–2.30, p = 0.038), vascular invasion (HR: 2.37, 95% CI: 1.18–4.76, p = 0.038), extrahepatic recurrence (HR: 2.14, 95% CI: 1.16–3.92, p = 0.015), and higher ALBI grade (at the time of recurrence) (HR: 2.18, 95% CI: 1.54–3.08, p < 0.001) were associated with shorter PRS, while curative treatment after recurrence (HR: 0.59, 95% CI: 0.38–0.92, p = 0.020) was associated with longer PRS (Table 3). Although patients under close surveillance after MWA had less extrahepatic recurrence (6.6% vs. 21.8%, p = 0.001), more early-stage recurrence (81.8% vs. 66.3%, p= 0.008), less vascular invasion (1.7% vs. 13.9%, p< 0.001) and had more candidates for curative treatment (80.2% vs. 70.3%, p= 0.037) (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000536542), surveillance interval did not affect the PRS (p= 0.288) in our study.

Table 3.

Univariate and multivariate Cox regression analyses of prognostic factors of PRS

VariablesHR comparisonUnivariate analysisMultivariate analysis
HR (95% CI)p valueHR (95% CI)p value
Sex Male versus female 1.07 (0.71–1.60) 0.747   
Etiology HBV versus non-HBV 0.89 (0.57–1.38) 0.591   
Time to recurrence, years ≤2 versus >2 1.12 (0.79–1.58) 0.528   
Age at recurrence, years >60 versus ≤60 0.77 (0.55–1.08) 0.126   
Cirrhosis at diagnosis of recurrence Yes versus no 0.91 (0.56–1.48) 0.711   
Portal hypertension at diagnosis of recurrence Yes versus no 1.24 (0.86–1.78) 0.253   
Tumor number at recurrence Multiple versus single 1.88 (1.32–2.67) <0.001 1.54 (1.03–2.30) 0.038 
AFP level at recurrence, ng/mL ≥400 versus < 400 1.38 (0.93–2.06) 0.107   
Recurrence patterns Extrahepatic ± intrahepatic versus only intrahepatic 4.39 (2.82–6.83) <0.001 2.14 (1.16–3.92) 0.015 
Vascular invasion Yes versus no 4.81 (2.79–8.30) <0.001 2.37 (1.18–4.76) 0.038 
BCLC tumor staging of the initial tumor Stage B versus 0/A 1.21 (0.75–1.95) 0.426   
Extent of recurrence Beyond versus within Milan criteria 3.20 (2.20–4.66) <0.001   
ALBI grade at recurrence Grade 2, 3 versus 1 2.00 (1.43–2.81) <0.001 2.18 (1.54–3.08) <0.001 
NLR at recurrence >2.5 versus ≤2.5 1.38 (0.98–1.93) 0.064   
Treatment modalities for recurrence Curative versus non-curative treatment 0.34 (0.24–0.49) <0.001 0.59 (0.38–0.92) 0.020 
Follow-up schedule 6- versus 3-monthly surveillance 1.20 (0.86–1.67) 0.294   
VariablesHR comparisonUnivariate analysisMultivariate analysis
HR (95% CI)p valueHR (95% CI)p value
Sex Male versus female 1.07 (0.71–1.60) 0.747   
Etiology HBV versus non-HBV 0.89 (0.57–1.38) 0.591   
Time to recurrence, years ≤2 versus >2 1.12 (0.79–1.58) 0.528   
Age at recurrence, years >60 versus ≤60 0.77 (0.55–1.08) 0.126   
Cirrhosis at diagnosis of recurrence Yes versus no 0.91 (0.56–1.48) 0.711   
Portal hypertension at diagnosis of recurrence Yes versus no 1.24 (0.86–1.78) 0.253   
Tumor number at recurrence Multiple versus single 1.88 (1.32–2.67) <0.001 1.54 (1.03–2.30) 0.038 
AFP level at recurrence, ng/mL ≥400 versus < 400 1.38 (0.93–2.06) 0.107   
Recurrence patterns Extrahepatic ± intrahepatic versus only intrahepatic 4.39 (2.82–6.83) <0.001 2.14 (1.16–3.92) 0.015 
Vascular invasion Yes versus no 4.81 (2.79–8.30) <0.001 2.37 (1.18–4.76) 0.038 
BCLC tumor staging of the initial tumor Stage B versus 0/A 1.21 (0.75–1.95) 0.426   
Extent of recurrence Beyond versus within Milan criteria 3.20 (2.20–4.66) <0.001   
ALBI grade at recurrence Grade 2, 3 versus 1 2.00 (1.43–2.81) <0.001 2.18 (1.54–3.08) <0.001 
NLR at recurrence >2.5 versus ≤2.5 1.38 (0.98–1.93) 0.064   
Treatment modalities for recurrence Curative versus non-curative treatment 0.34 (0.24–0.49) <0.001 0.59 (0.38–0.92) 0.020 
Follow-up schedule 6- versus 3-monthly surveillance 1.20 (0.86–1.67) 0.294   

The bold p values represent the significance between the two groups.

NLR, neutrophil-lymphocyte ratio; HBV, hepatitis B virus; ALBI, albumin-bilirubin; AFP, α-fetoprotein; BCLC, Barcelona clinic liver cancer; PRS, post-recurrence survival.

We further performed subgroup analyses according to abovementioned prognostic factors and confirmed that tumor number, vascular invasion, extrahepatic recurrence, ALBI grade, and treatment modalities for recurrence were independent prognostic factors of PRS for patients with early and late recurrence (Fig. 2). No significant differences of PRS were observed between patients with early and late recurrence regardless of the subgrouping strategies (all p > 0.05).

Fig. 2.

Kaplan-Meier curves in patients with recurrent hepatocellular carcinoma (HCC) with different prognostic factors. a Recurrent tumor number. b Recurrence patterns. c Vascular invasion. d ALBI grade. e Treatment modalities; ERHCC, early recurrent HCC; LRHCC, late recurrent HCC; ALBI, albumin-bilirubin.

Fig. 2.

Kaplan-Meier curves in patients with recurrent hepatocellular carcinoma (HCC) with different prognostic factors. a Recurrent tumor number. b Recurrence patterns. c Vascular invasion. d ALBI grade. e Treatment modalities; ERHCC, early recurrent HCC; LRHCC, late recurrent HCC; ALBI, albumin-bilirubin.

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In this retrospective study, we assessed the recurrence patterns, treatment modalities, and PRS of patients with HCC recurrence following MWA. We found that sex, age, etiology, liver functions, performance status, initial tumor status, and ALBI grade of the patients did not affect the time to recurrence after MWA. NLR before MWA was the only factor associated with early recurrence, suggesting that systemic inflammation was an important factor for HCC recurrence. Pre-treatment NLR has been suggested as an important prognostic factor for HCC patients who underwent SR or liver transplantation [17]. The study by Ni et al. [18] confirmed that both pre- and post-treatment NLRs were an independent factor for early recurrence after radiofrequency ablation of HCC. Another study identified increase in NLR after MWA as a risk factor for local HCC recurrence [19]. Whether NLR before and after MWA could be used for recurrence risk stratification in HCC patients treated with MWA needs more study to confirm.

According to the previous studies, patients with early recurrence were more likely to recur at extrahepatic sites, more vascular invasion, more tumors outside the Milan criteria and less likely to have the recurrence treated with curative treatment than those with late recurrence after surgery or transplantation [13, 20, 21]. However, we found no significant differences in the recurrence patterns and post-recurrence treatments between early and late recurrence after MWA of HCC. This could be explained by the differences in the treatment options for initial HCC. Early recurrence is more likely due to dissemination of the primary HCC, while late recurrence is de novo cancer [12, 22]. SR and liver transplantation seemed to be more “curative” than MWA, as previous studies suggested that they provided more favorable recurrence-free survival than ablation [4, 23, 24]. Similarly, previous studies showed that patients with early HCC recurrence after SR had worse PRS than those with late recurrence [13‒15, 20]. In the present study, patients with early HCC recurrence after MWA had comparable PRS as patients with late recurrence. In our study cohort, majority of the recurrent tumors were in very early or early stage, and were amenable for curative treatment, which might explain the lack of the differences in PRS.

A number of factors have been reported to be associated with a poor PRS in patients following curative treatment. The most consistently reported risk factors of PRS included AFP level at recurrence, tumor burden, vascular invasion, and treatment strategies [25, 26]. Majority of these studies were in patients with recurrent HCC after SR or liver transplantation. In the present study, multiple recurrent tumors, vascular invasion, extrahepatic recurrence, higher ALBI grade, and whether patients were treated with curative method were independent prognostic factors of PRS. The prognostic value of ALBI grade was confirmed for PRS in HCC patients treated with MWA. ALBI grade incorporated both serum albumin and total bilirubin and could provide a simple and objective method for assessing liver function with good prognostic performance in HCC patients. Liu et al. [27] found that ALBI grade could predict survival for HCC across different treatment modalities and BCLC staging. Qi et al. [28] found that ALBI grade impacted PRS for patients with recurrent HCC who received MWA. In our study, tumor burden, liver function, and treatment modalities were all independently associated with PRS regardless of time to recurrence. The optimal treatment of recurrent HCC after MWA should be determined by taking both recurrent tumor characteristics and patients’ liver function status into consideration.

As curative treatment after recurrence provided better PRS in our study and previous studies [29, 30], we also included the surveillance interval in multivariate analyses. We found that patients under close surveillance had a lower incidence of extrahepatic recurrence and higher chance to receive curative treatment compared with those under regular surveillance, but surveillance interval had no significant effect on PRS. Close patient HCC surveillance with imaging examinations every 3–4 months has been recommended by some studies and suggested to improve HCC survival [3, 31‒33]. Conversely, some investigators failed to detect a beneficial effect of more intensive surveillance on prognosis [34, 35]. The lack of beneficial effect of close surveillance on PRS in our study may be due to relatively small sample size or lack of risk stratification [31, 34].

There are some limitations in the present study. Firstly, it is a retrospective study within a tertiary hospital, and selection bias of the patients existed due to the nature of the study. Multi-center prospective study would provide more data with better evidence power. Secondly, no risk stratification was performed in the present study as there is no well-established risk model. Finally, the etiology of the patients was mainly hepatitis virus B infection; therefore, HCC caused by hepatitis C virus, alcohol, non-fatty liver disease, or autoimmune liver disease may behave differently.

Majority of recurrent HCC after MWA were intrahepatic-only recurrence, within the Milan criteria, and suitable for potentially curative treatment. Early recurrence and late recurrence had similar recurrence patterns, post-recurrence treatments, and PRS. Tumor burden and patients’ liver function reserve were independent prognostic factors of PRS in recurrent HCC and should be considered to decide the optimal post-recurrence treatment.

This retrospective study was approved by the XiJing Hospital of Digestive Disease (No. KY20221056-C-6) and conducted according to the ethical guidelines of the 1975 Declaration of Helsinki. The need for a written informed consent was waived by the XiJing Hospital of Digestive Disease.

None of the authors have a conflict of interest to disclose.

This study was supported by Key Research and Development Program of Shaanxi (No. 2022ZDLSF03-03 and No. 2023-ZDLSF-33) and National Natural Science Foundation of China (No. 81820108005).

All authors have contributed to the work and commented on previous versions of the manuscript. Data collection and analysis were performed by Jing Zhang, Guanya Guo, and Tao Li. The first draft of the manuscript was written by Jing Zhang and Guanya Guo. Scientific advisors: Jing Zhang, Changcun Guo, and Xinmin Zhou. Critical revision of the article for important intellectual content: Changcun Guo, Ying Han, and Xinmin Zhou. Financial support: Ying Han and Xinmin Zhou.

Additional Information

Jing Zhang, Guanya Guo, Tao Li, Changcun Guo, Ying Han, and Xinmin Zhou contributed equally to this work.

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author Zhou upon reasonable request.

1.
Forner
A
,
Reig
M
,
Bruix
J
.
Hepatocellular carcinoma
.
Lancet
.
2018
;
391
(
10127
):
1301
14
. .
2.
Xie
DY
,
Ren
ZG
,
Zhou
J
,
Fan
J
,
Gao
Q
.
2019 Chinese clinical guidelines for the management of hepatocellular carcinoma: updates and insights
.
Hepatobiliary Surg Nutr
.
2020
;
9
(
4
):
452
63
. .
3.
European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu
;
European Association for the Study of the Liver
.
EASL clinical practice guidelines: management of hepatocellular carcinoma
.
J Hepatol
.
2018
;
69
(
1
):
182
236
. .
4.
Liu
W
,
Zou
R
,
Wang
C
,
Qiu
J
,
Shen
J
,
Liao
Y
, et al
.
Microwave ablation versus resection for hepatocellular carcinoma within the Milan criteria: a propensity-score analysis
.
Ther Adv Med Oncol
.
2019
;
11
:
1758835919874652
. .
5.
Zhang
M
,
Ma
H
,
Zhang
J
,
He
L
,
Ye
X
,
Li
X
.
Comparison of microwave ablation and hepatic resection for hepatocellular carcinoma: a meta-analysis
.
Onco Targets Ther
.
2017
;
10
:
4829
39
. .
6.
Li
W
,
Zhou
X
,
Huang
Z
,
Zhang
K
,
Luo
X
,
Zhong
J
, et al
.
Short-term and long-term outcomes of laparoscopic hepatectomy, microwave ablation, and open hepatectomy for small hepatocellular carcinoma: a 5-year experience in a single center
.
Hepatol Res
.
2017
;
47
(
7
):
650
7
. .
7.
Bailey
CW
,
Sydnor
MK
Jr
.
Current state of tumor ablation therapies
.
Dig Dis Sci
.
2019
;
64
(
4
):
951
8
. .
8.
Yu
J
,
Liang
P
.
Status and advancement of microwave ablation in China
.
Int J Hyperthermia
.
2017
;
33
(
3
):
278
87
. .
9.
Wei
CY
,
Chau
GY
,
Chen
PH
,
Liu
CA
,
Huang
YH
,
Huo
TI
, et al
.
A comparison of prognoses between surgical resection and radiofrequency ablation therapy for patients with hepatocellular carcinoma and esophagogastric varices
.
Sci Rep
.
2020
;
10
(
1
):
17259
. .
10.
Bosi
C
,
Rimini
M
,
Casadei-Gardini
A
,
Giorgio
E
.
Understanding the causes of recurrent HCC after liver resection and radiofrequency ablation
.
Expert Rev Anticancer Ther
.
2023
;
23
(
5
):
503
15
. .
11.
Lee
HA
,
Lee
YS
,
Kim
BK
,
Jung
YK
,
Kim
SU
,
Park
JY
, et al
.
Change in the recurrence pattern and predictors over time after complete cure of hepatocellular carcinoma
.
Gut Liver
.
2021
;
15
(
3
):
420
9
. .
12.
Yang
Y
,
Chen
Y
,
Ye
F
,
Cao
X
,
Xin
Y
,
Wang
Y
, et al
.
Late recurrence of hepatocellular carcinoma after radiofrequency ablation: a multicenter study of risk factors, patterns, and survival
.
Eur Radiol
.
2021
;
31
(
5
):
3053
64
. .
13.
Wang
MD
,
Li
C
,
Liang
L
,
Xing
H
,
Sun
LY
,
Quan
B
, et al
.
Early and late recurrence of hepatitis B virus-associated hepatocellular carcinoma
.
Oncologist
.
2020
;
25
(
10
):
e1541
51
. .
14.
Xing
H
,
Sun
LY
,
Yan
WT
,
Quan
B
,
Liang
L
,
Li
C
, et al
.
Repeat hepatectomy for patients with early and late recurrence of hepatocellular carcinoma: a multicenter propensity score matching analysis
.
Surgery
.
2021
;
169
(
4
):
911
20
. .
15.
Wang
WQ
,
Lv
X
,
Li
J
,
Li
J
,
Wang
JL
,
Yuan
T
, et al
.
Repeat hepatectomy versus microwave ablation for solitary and small (≤3 cm) recurrent hepatocellular carcinoma with early or late recurrence: a propensity score matched study
.
Eur J Surg Oncol
.
2023
;
49
(
5
):
1001
8
. .
16.
Yang
Y
,
Xin
Y
,
Ye
F
,
Liu
N
,
Zhang
X
,
Wang
Y
, et al
.
Early recurrence after radiofrequency ablation for hepatocellular carcinoma: a multicenter retrospective study on definition, patterns and risk factors
.
Int J Hyperthermia
.
2021
;
38
(
1
):
437
46
. .
17.
Najjar
M
,
Agrawal
S
,
Emond
JC
,
Halazun
KJ
.
Pretreatment neutrophil-lymphocyte ratio: useful prognostic biomarker in hepatocellular carcinoma
.
J Hepatocell Carcinoma
.
2018
;
5
:
17
28
. .
18.
Ni
Z
,
Wu
B
,
Liu
Z
,
Wang
Q
,
Han
X
,
Cheng
W
, et al
.
Clinical value of combined preoperative-postoperative neutrophil-to-lymphocyte ratio in predicting hepatocellular carcinoma prognosis after radiofrequency ablation
.
Br J Radiol
.
2023
;
96
(
1145
):
20220887
. .
19.
Della Corte
A
,
Sallemi
C
,
Ratti
F
,
Monfardini
L
,
Gusmini
S
,
Cipriani
F
, et al
.
Retrospective evaluation and significance of neutrophil-to-lymphocyte ratio prior to and 1 month following microwave ablation of hepatocellular carcinoma
.
Cardiovasc Intervent Radiol
.
2023
;
46
(
1
):
49
59
. .
20.
Wei
T
,
Zhang
XF
,
Bagante
F
,
Ratti
F
,
Marques
HP
,
Silva
S
, et al
.
Early versus late recurrence of hepatocellular carcinoma after surgical resection based on post-recurrence survival: an international multi-institutional analysis
.
J Gastrointest Surg
.
2021
;
25
(
1
):
125
33
. .
21.
El-Domiaty
N
,
Saliba
F
,
Vibert
E
,
Karam
V
,
Sobesky
R
,
Ibrahim
W
, et al
.
Early versus late hepatocellular carcinoma recurrence after transplantation: predictive factors, patterns, and long-term outcome
.
Transplantation
.
2021
;
105
(
8
):
1778
90
. .
22.
Xu
XF
,
Xing
H
,
Han
J
,
Li
ZL
,
Lau
WY
,
Zhou
YH
, et al
.
Risk factors, patterns, and outcomes of late recurrence after liver resection for hepatocellular carcinoma: a multicenter study from China
.
JAMA Surg
.
2019
;
154
(
3
):
209
17
. .
23.
Shin
SW
,
Ahn
KS
,
Kim
SW
,
Kim
TS
,
Kim
YH
,
Kang
KJ
.
Liver resection versus local ablation therapies for hepatocellular carcinoma within the milan criteria: a systematic review and meta-analysis
.
Ann Surg
.
2021
;
273
(
4
):
656
66
. .
24.
Habibollahi
P
,
Sheth
RA
,
Cressman
ENK
.
Histological correlation for radiofrequency and microwave ablation in the local control of hepatocellular carcinoma (HCC) before liver transplantation: a comprehensive review
.
Cancers
.
2020
;
13
(
1
):
104
. .
25.
Saito
R
,
Amemiya
H
,
Hosomura
N
,
Kawaida
H
,
Maruyama
S
,
Shimizu
H
, et al
.
Prognostic factors for post-recurrent survival in hepatocellular carcinoma after curative resection
.
Anticancer Res
.
2019
;
39
(
6
):
3033
8
. .
26.
Tsilimigras
DI
,
Moris
D
,
Hyer
JM
,
Bagante
F
,
Ratti
F
,
Marques
HP
, et al
.
Serum α-fetoprotein levels at time of recurrence predict post-recurrence outcomes following resection of hepatocellular carcinoma
.
Ann Surg Oncol
.
2021
;
28
(
12
):
7673
83
. .
27.
Liu
PH
,
Hsu
CY
,
Hsia
CY
,
Lee
YH
,
Chiou
YY
,
Huang
YH
, et al
.
ALBI and PALBI grade predict survival for HCC across treatment modalities and BCLC stages in the MELD Era
.
J Gastroenterol Hepatol
.
2017
;
32
(
4
):
879
86
. .
28.
Qi
C
,
Li
S
,
Zhang
L
.
Development and validation of a clinicopathological-based nomogram to predict the survival outcome of patients with recurrent hepatocellular carcinoma after hepatectomy who underwent microwave ablation
.
Cancer Manag Res
.
2020
;
12
:
7589
600
. .
29.
Al-Ameri
A
,
Yu
X
,
Zheng
S
.
Predictors of post-recurrence survival in hepatocellular carcinoma patients following liver transplantation: systematic review and meta-analysis
.
Transplant Rev
.
2022
;
36
(
1
):
100676
. .
30.
Na
GH
,
Hong
TH
,
You
YK
,
Kim
DG
.
Clinical analysis of patients with hepatocellular carcinoma recurrence after living-donor liver transplantation
.
World J Gastroenterol
.
2016
;
22
(
25
):
5790
9
. .
31.
Lee
M
,
Chang
Y
,
Oh
S
,
Cho
YY
,
Jung
DE
,
Kim
HH
, et al
.
Assessment of the surveillance interval at 1 year after curative treatment in hepatocellular carcinoma: risk stratification
.
Gut Liver
.
2018
;
12
(
5
):
571
82
. .
32.
Tampaki
M
,
Papatheodoridis
GV
,
Cholongitas
E
.
Intrahepatic recurrence of hepatocellular carcinoma after resection: an update
.
Clin J Gastroenterol
.
2021
;
14
(
3
):
699
713
. .
33.
Papaconstantinou
D
,
Tsilimigras
DI
,
Pawlik
TM
.
Recurrent hepatocellular carcinoma: patterns, detection, staging and treatment
.
J Hepatocell Carcinoma
.
2022
;
9
:
947
57
. .
34.
Sun
X
,
Li
L
,
Lyu
N
,
Mu
L
,
Lai
J
,
Zhao
M
.
Follow-up schedule for initial recurrent hepatocellular carcinoma after ablation based on risk classification
.
Cancer Imag
.
2020
;
20
(
1
):
42
. .
35.
Hyder
O
,
Dodson
RM
,
Weiss
M
,
Cosgrove
DP
,
Herman
JM
,
Geschwind
JFH
, et al
.
Trends and patterns of utilization in post-treatment surveillance imaging among patients treated for hepatocellular carcinoma
.
J Gastrointest Surg
.
2013
;
17
(
10
):
1774
83
. .