|Year : 2021 | Volume
| Issue : 6 | Page : 273-279
Risk factors for early and late recurrence in hepatocellular carcinoma after liver transplantation
Fan Hsiu-Lung1, Hsieh Chung-Bao1, Kuo Shih-Ming2, Chen Teng-Wei1
1 Department of Surgery, Division of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
2 Department of Surgery, Division of Pediatric Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
|Date of Submission||01-Jun-2020|
|Date of Decision||18-Nov-2020|
|Date of Acceptance||17-Feb-2021|
|Date of Web Publication||06-Jul-2021|
Dr. Chen Teng-Wei
Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei
Source of Support: None, Conflict of Interest: None
Background: Risk factors of early and late recurrence in hepatocellular carcinoma (HCC) after liver transplantation (LT) remain unclear. Aim: To identify factors that affect, both early and late recurrence in this setting. Methods: We retrospectively analyzed outcomes of 220 patients with HCC who received LT. Two patients who underwent re-transplantation were excluded. Early, late, and very late recurrence were defined as recurrence in the 1st year, 1–5 years, and >5 years after LT, respectively. Kaplan–Meier survival curves were generated, and log-rank tests were performed to compare survival between these groups. Univariate and multivariate Cox proportional-hazard models for risks of early and late recurrence were established. Results: Twenty and 19 patients experienced HCC recurrence in the 1st year and between 1 and 5 years, respectively, after undergoing LT. The groups differed significantly in cumulative postrecurrence survival rate. The hazard ratio of early recurrence for tumor size >3 cm was 1.766 (P = 0.046) and that for tumor number >3 was 1.929 (P = 0.027). Alpha-fetoprotein >20 ng/mL was a predictor of early recurrence in multivariate analysis (P = 0.077). The hazard ratio of late recurrence for HCC with microvascular invasion was 1.891 (P = 0.047). Conclusion: The recurrence rate of HCC was high in the 1st year after LT. Patients with early recurrence had a poorer survival rate than those with late recurrence. Tumor size >3 cm and tumor number >3 were risk factors of early recurrence. Microvascular invasion was a risk factor for late recurrence. Close individual surveillance is needed in patients with these risk factors.
Keywords: Hepatocellular carcinoma, risk factors, liver transplantation, recurrence
|How to cite this article:|
Hsiu-Lung F, Chung-Bao H, Shih-Ming K, Teng-Wei C. Risk factors for early and late recurrence in hepatocellular carcinoma after liver transplantation. J Med Sci 2021;41:273-9
|How to cite this URL:|
Hsiu-Lung F, Chung-Bao H, Shih-Ming K, Teng-Wei C. Risk factors for early and late recurrence in hepatocellular carcinoma after liver transplantation. J Med Sci [serial online] 2021 [cited 2022 Jan 28];41:273-9. Available from: https://www.jmedscindmc.com/text.asp?2021/41/6/273/320797
| Introduction|| |
Hepatocellular carcinoma (HCC) is the 5th most common malignancy in the world. Surgical and curative treatments include liver resection and liver transplantation (LT). LT is theoretically the optimal treatment because of simultaneous removal of cirrhotic liver and HCC. Many selection criteria for LT in HCC patients have been established to achieve acceptable outcomes, such as the Milan criteria and University of California San Francisco (UCSF) criteria., The recurrence rate after LT remains 8%–17.4%.,,, The identification of additional risk factors for HCC recurrence after LT is needed.
The major risk factors for recurrence after LT include tumor size, tumor number, and macrovascular invasion. These factors are considered in the Milan and USCF criteria for selection of HCC patients for LT. In the UCSF criteria, other risk factors include alpha-fetoprotein (AFP) level, tumor spreading with total hepatectomy, immunosuppression, and prescription of targeted therapy. Risk factors for recurrence after liver resection have been extensively studied and further divided into risk factors for early and late recurrence. Risk factors for early and late recurrence after LT are rarely discussed in the literature. Our aim in this study was to analyze the risk factors of early and late recurrence in HCC patients who underwent LT.
| Materials and Methods|| |
Between August 2003 and August 2019, 220 HCC patients underwent LT and received follow-up management in our institution. Selection criteria for LT in the HCC patients were the Milan criteria for deceased donor LT and the UCSF criteria for living-donor LT. The records of these patients were retrospectively reviewed. Two patients who underwent re-transplantation were excluded. The time of tumor recurrence was established through follow-up studies. Early recurrence was defined as recurrence in the 1st year after LT, and late recurrence was defined as recurrence in 1–5 years after LT. Very late recurrence was defined as recurrence >5 years after LT. Recipient characteristics including age, gender, underlying liver disease, signs of decompensated liver cirrhosis (ascites, hepatic encephalopathy, and bleeding), preoperative serum biochemistry results (total bilirubin, creatinine, ammonia, albumin, and glucose), international normalized ratio, blood platelet count, model for end-stage liver disease score, AFP level, operative factors (surgery type in deceased donor LT, living donor LT, split LT, graft weight, blood loss, and operative time), and pathologic results (tumor size, tumor number, large vessel invasion, microvascular invasion, and differentiation) were recorded.
Post-LT follow-up evaluations including monitoring of AFP level and abdominal sonography were performed every 3 months. If the level of AFP increased, a dynamic computed tomography scan of liver was performed. Chest radiographs were performed once a year. A brain computed tomography scan was performed in patients with severe headaches or neurologic symptoms, and whole-body bone scans were performed in patients with severe bone pain. Positron emission tomography scans were performed if the above studies were normal, but AFP level was elevated. The site of recurrence and the time of patient death were established through follow-up studies. The study was approved by the institutional review board of Tri-Service General Hospital (Research institution: Tri-Service General Hospital; Approval number: TSGHIRB No.: C202005076; Approval date: 2020/5/7).
Continuous variables were presented as median (interquartile range), and categorical variables were expressed as the number (percentage) of events. To test for differences between early-recurrence and late-recurrence groups, the Mann–Whitney U-test and Chi-square test were used. If 20% of the cells had expected numbers <5, the Chi-square test was replaced with Fisher's exact test. To determine the variables associated with early recurrence, univariate, and multivariate Cox proportional hazard models were established. All factors with a P < 0.1 in the univariate analysis were put into a reverse multivariate hazard model. The postrecurrence survival duration was calculated from the date of recurrence to the date of death or the end of follow-up. Kaplan–Meier survival curves were generated, and a log-rank test was performed to compare group survival status. All two-sided statistical analyses were performed using SPSS 15.0 statistical software, (SPSS Inc., Chicago, IL, USA). Significance was defined as P < 0.05.
| Results|| |
Of the 218 patients included in this study, 42 patients (19.2%) had tumor recurrence after LT. The time of recurrence after LT is presented in [Figure 1]. Twenty patients had recurrence in the 1st year after LT, 6 patients in 1–2 years after LT, 6 patients in 2–3 years after LT, 7 patients in 3–4 years after LT, and 3 patients ≥5 years after LT. Twenty (47.6%) recipients experienced tumor recurrence in the 1st year after LT. The rate of recurrence 1–2 years after LT steeply decreased to 14.2%. Nineteen recipients were assigned to the early-recurrence group, 20 were assigned to the late-recurrence group, and 3 recipients were assigned to the very late-recurrence group. The average follow-up duration was 37 months (range, 2–135 months).
The sites of recurrence are presented in [Figure 2]. In the early-recurrence group, 45% of patients had intra-hepatic recurrence, and 55% had extra-hepatic recurrence. In the late-recurrence group, 32% of patients had intra-hepatic recurrence, and 68% had extra-hepatic recurrence. At the end of the follow-up period, only five patients (25%) were alive in the early-recurrence group and only nine patients (47.4%) were alive in the late-recurrence group. The three groups differed significantly in cumulative postrecurrence survival rate [Figure 3].
|Figure 3: Cumulative post-recurrence survival rate in earl, late, very later recurrence group|
Click here to view
The three recipients in the very late-recurrence group were excluded from further analysis because of the small number of patients. Patients' characteristics are summarized in [Table 1]. Patients in early-recurrence and late-recurrence groups did not differ with regard to age, gender, underlying liver disease, signs of portal hypertension, preoperative serum biochemistry results, international normalized ratio, blood platelet count, model for end-stage liver disease score, operative factors, or pathologic results. Preoperative AFP levels were higher in the early-recurrence group than in the late-recurrence group, although this difference was not statistically significant (P = 0.070).
The results of Cox proportional hazard analysis for early recurrence are presented in [Table 2]. Tumor size >3 cm and tumor number >3 were the main predictors of early recurrence (P < 0.05). When compared to that of patients with tumor size ≤3 cm, the hazard ratio of early recurrence for patients with tumor size >3 cm was 1.766 (95% confidence interval [CI], 1.011–3.086; P = 0.046). When compared to that of patients with tumor number ≤3, the hazard ratio of early recurrence for patients with tumor number >3 was 1.929 (95% CI, 1.076–3.460; P = 0.027). AFP level >20 ng/mL was a significant risk factor of early recurrence in univariate analysis and only showed a trend of early recurrence in multivariate analysis (P = 0.077). Residual tumor in explanted liver, pathologic great vessel invasion, and microvascular invasion were significant risk factors of early recurrence in univariate analysis; however, these effects were no longer evident in multivariate analysis.
The results of the Cox proportional hazard analysis for late recurrence are presented in [Table 3]. Microvascular invasion was the main risk factor for late recurrence (P < 0.05). When compared to HCC without microvascular invasion, the hazard ratio of late recurrence for HCC with microvascular invasion was 1.891 (95% CI, 1.008–3.547; P = 0.047). Tumor number >3 was a significant risk factor of late recurrence in univariate analysis; however, this effect was no longer evident in multivariate analysis.
| Discussion|| |
Risk factors for early and late recurrence are theoretically different, and these differences can inform clinicians regarding individual surveillance at distinct time points after LT. Twenty (47.6%) recipients in the current study experienced tumor recurrence in the 1st year after LT. Patients with early recurrence rapidly progressed to death within 2 years. Tumor number and tumor size were important risk factors for early recurrence. Conversely, microvascular invasion was the main predictor of late recurrence.
The definitions of early and late recurrence are still controversial. In patients undergoing liver resection for HCC in previous studies, the peak of early recurrence was within the first 2 years after surgery., This led to the definition of early recurrence after LT as those occurring within 2 years after surgery. In another study, average time to recurrence was 15.1 months after LT. A 2-year threshold between early and late is reasonable given these observations. However, a high-volume LT center in South Korea published a study in 2018, which established a 1-year threshold after LT between early and late recurrence. In the current study, about 50% of recipients experienced tumor recurrence in the 1st year after LT. The rate of recurrence 1–2 years after LT steeply decreased to 14.2%. This result was consistent with the published data from the above-mentioned LT center in South Korea. Thus, close monitoring should be done in the 1st year after LT.
Tumor number and tumor size have been verified as key factors associated with outcome after LT among HCC patients. Almost all selection criteria list tumor size and tumor number as parameters, including Milan criteria, UCSF criteria, Asan criteria, up to seven criteria, Kyoto criteria, Tokyo criteria, Samsung criteria, and Kyushu criteria. In this study, tumor number and size have again been verified as important risk factors for early recurrence. In particular, a maximum tumor size >3 cm and tumor number >3 were significant risk factors. The maximum tumor size and tumor number were different compared to those in the above-mentioned selection criteria. These criteria were designed for expanding the number of eligible candidates and not for analyzing the risk of recurrence. Therefore, the tumor size and number in the above-mentioned selection criteria were larger than in this study. Undoubtedly, tumor size and number are the most important risk factors associated with outcome in HCC patients after LT.
It has been suggested that tumor size and number alone do not sufficiently represent tumor behaviors. The concept of adding potential biomarkers to selection criteria has been contemplated. AFP level ≤1000 ng/mL is listed among Samsung criteria. AFP level ≤400 ng/mL is listed among total tumor volume and AFP criteria. In this study, AFP level >20 ng/mL was a significant risk factor for early recurrence in univariate analysis and only showed a trend for early recurrence in multivariate analysis. This study suggests that HCC patients with AFP level >20 ng/mL prior to LT should be under strict surveillance in the 1st year after LT.
The prognosis of patients with early recurrence has been shown to be worse than that of patients with late recurrence. Similar results demonstrating poor outcome in patients with early recurrence after LT were reported from a large-volume hospital in South Korea. Our study reports similar results as those of this previous study. The identification of risk factors and establishing proper selection criteria are needed for optimal management of HCC patients after LT.
A limitation of this study is that the size of residual viable tumors after locoregional treatment was difficult to measure on the operative day of LT. This was because the percentage of necrosis was difficult to evaluate after locoregional treatments such as transarterial chemoembolization or radiofrequency ablation before LT.
| Conclusion|| |
A high recurrence rate was observed in the 1st year after LT in HCC patients. Patients with early recurrence had poorer survival than those with late recurrence. Tumor size >3 cm and tumor number >3 were risk factors for early recurrence. Microvascular invasion was a risk factor for late recurrence. Close individual surveillance is needed for patients with these risk factors.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018;391:1301-14.
Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al
. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-9.
Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al
. Liver transplantation for hepatocellular carcinoma: Expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394-403.
Chok KS, Chan SC, Cheung TT, Chan AC, Fan ST, Lo CM. Late recurrence of hepatocellular carcinoma after liver transplantation. World J Surg 2011;35:2058-62.
Alshahrani AA, Ha SM, Hwang S, Ahn CS, Kim KH, Moon DB, et al
. Clinical features and surveillance of very late hepatocellular carcinoma recurrence after liver transplantation. Ann Transplant 2018;23:659-65.
Toso C, Meeberg G, Hernandez-Alejandro R, Dufour JF, Marotta P, Majno P, et al
. Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: A prospective validation. Hepatology 2015;62:158-65.
Yoon YI, Lee SG. Living donor liver transplantation for hepatocellular carcinoma: An Asian perspective. Dig Dis Sci 2019;64:993-1000.
Toso C, Meeberg GA, Bigam DL, Oberholzer J, Shapiro AM, Gutfreund K, et al
. De novo
sirolimus-based immunosuppression after liver transplantation for hepatocellular carcinoma: Long-term outcomes and side effects. Transplantation 2007;83:1162-8.
Alsina AE, Makris A, Nenos V, Sucre E, Arrobas J, Franco E, et al
. Can sorafenib increase survival for recurrent hepatocellular carcinoma after liver transplantation? A pilot study. Am Surg 2014;80:680-4.
Colecchia A, Schiumerini R, Cucchetti A, Cescon M, Taddia M, Marasco G, et al
. Prognostic factors for hepatocellular carcinoma recurrence. World J Gastroenterol 2014;20:5935-50.
Cucchetti A, Piscaglia F, Caturelli E, Benvegnù L, Vivarelli M, Ercolani G, et al
. Comparison of recurrence of hepatocellular carcinoma after resection in patients with cirrhosis to its occurrence in a surveilled cirrhotic population. Ann Surg Oncol 2009;16:413-22.
Poon RT. Differentiating early and late recurrences after resection of HCC in cirrhotic patients: Implications on surveillance, prevention, and treatment strategies. Ann Surg Oncol 2009;16:792-4.
Davis E, Wiesner R, Valdecasas J, Kita Y, Rossi M, Schwartz M. Treatment of recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl 2011;17 Suppl 2:S162-6.
Lee SG, Hwang S, Moon DB, Ahn CS, Kim KH, Sung KB, et al
. Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at one large-volume center. Liver Transpl 2008;14:935-45.
Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, et al
. Metroticket Investigator Study Group. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: A retrospective, exploratory analysis. Lancet Oncol 2009;10:35-43.
Kaido T, Ogawa K, Mori A, Fujimoto Y, Ito T, Tomiyama K, et al
. Usefulness of the Kyoto criteria as expanded selection criteria for liver transplantation for hepatocellular carcinoma. Surgery 2013;154:1053-60.
Akamatsu N, Sugawara Y, Kokudo N. Living donor liver trans- plantation for patients with hepatocellular carcinoma. Liver Cancer 2014;3:108-18.
Kim JM, Kwon CH, Joh JW, Park JB, Lee JH, Kim GS, et al
. Expanded criteria for liver transplantation in patients with hepatocellular carcinoma. Transplant Proc 2014;46:726-9.
Uchiyama H, Itoh S, Yoshizumi T, Ikegami T, Harimoto N, Soejima Y, et al
. Living donor liver trans- plantation for hepatocellular carcinoma: Results of prospective patient selection by Kyushu University Criteria in 7 years. HPB (Oxford)2017;19:1082-90.
Poon RT, Fan ST, Ng IO, Lo CM, Liu CL, Wong J. Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer 2000;89:500-7.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]