- Email: [email protected]
Liver transplantation for hepatocellular carcinoma: is zero recurrence theoretically possible?
HCC recurrence after liver transplantation Original Article / Transplantation
Liver transplantation for hepatocellular carcinoma: is zero recurrence theoretically possible? Sabine Irtan, Louise Barbier, Claire Francoz, Federica Dondéro, François Durand and Jacques Belghiti Clichy, France
BACKGROUND: Hepatocellular carcinoma (HCC) recurrence KEY WORDS: hepatocellular carcinoma; remains a key issue after liver transplantation. This study liver transplantation; aimed to determine a subgroup of HCC patients within the neoplasm recurrence; Milan criteria who could achieve a theoretical goal of zero resurvival rate currence rates after liver transplantation. METHODS: Between 1999 and 2009, 179 patients who received liver transplantation for HCC within the Milan criteria were retrospectively included. Analysis of the factors associated with HCC recurrence was performed to determine the subgroup of patients at the lowest risk of recurrence. RESULTS: Seventy-two percent of the patients received a bridging therapy, including 54 liver resections. Eleven (6.1%) patients recurred within a delay of 19±22 months and ultimately died. Factors associated with recurrence were serum alpha-fetoprotein level >400 ng/mL, satellite nodules, poor differentiation, microvascular invasion and cholangiocarcinoma component. Recurrence rates decreased from 6.1% to 3.1% in patients without any of these factors. CONCLUSIONS: Among HCC patients within the Milan criteria, selecting patients with factors based on histology would allow tending towards zero recurrence, and prior histological assessment by liver biopsy or resection may be essential to rule out poorly differentiated tumors, microvascular invasion, and cholangiocarcinoma component. (Hepatobiliary Pancreat Dis Int 2016;15:147-151)
Author Affiliations: Department of Hepato-Pancreato-Biliary Surgery (Irtan S, Barbier L, Dondéro F and Belghiti J) and Department of Hepatology (Francoz C and Durand F), Beaujon Hospital, Assistance PubliqueHôpitaux de Paris, University Denis Diderot-Paris VII, Clichy, France Corresponding Author: Louise Barbier, MD, Department of HepatoPancreato-Biliary Surgery, Beaujon Hospital, 100 Boulevard du Général Leclerc, 92118 Clichy Cedex, France (Tel: +33-1-4087-5895; Fax: +33-14087-1724; Email: [email protected]) © 2016, Hepatobiliary Pancreat Dis Int. All rights reserved. doi: 10.1016/S1499-3872(16)60069-3 Published online February 2, 2016.
Introduction
L
iver transplantation (LT) remains the best treatment of early hepatocellular carcinoma (HCC) developed on chronic liver disease. However, results are hampered by the long-lasting imbalance between an increasing number of candidates and graft shortage.[1] The unsatisfactory initial results of LT for clinically advanced HCC, together with the observation that small HCCs incidentally detected during surgery have an extremely low risk of post-LT recurrence, led to propose strict selection criteria.[2, 3] In this setting, the Milan criteria (single tumor ≤5 cm or 2-3 tumors ≤3 cm, in the absence of macroscopic vascular invasion) were adopted as guidelines for LT with the aim to achieve a 5-year overall survival rate of 70% and a recurrence rate of below 15%.[3] Increasing experience showed that some HCC patients beyond the Milan criteria, without vascular invasion or poorly differentiated HCC, demonstrated acceptable rates of survival and recurrence.[4] Several studies[5, 6] showed that high or rapidly increasing alpha-fetoprotein (AFP) levels were associated with increased recurrence. A study from a Toronto team showed that patients beyond the Milan criteria with AFP level >400 ng/mL and well differentiated HCC could achieve excellent results after LT.[7] On the other hand, even restricting LT for patients within the Milan criteria fails in completely ruling out post-LT for HCC recurrence[8] since some small HCCs have aggressive features such as poorly differentiated grade or vascular invasion.[9] In a context of graft shortage, a policy to select HCC candidates with post-LT outcomes similar to non-HCC recipients, while eliminating recurrence risk factors, should theoretically be considered. The
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aim of this study was therefore to determine a subgroup of AFP and/or presence of nodule at ultrasound led to of patients within the Milan criteria, which could theo- perform triple-phase computed tomography or magretically achieve a zero recurrence rate after LT. netic resonance imaging. HCC recurrence was defined as appearance of a new lesion with radiological features of HCC. Additional imaging techniques (bone scan, magnetic resonance imaging) were used if necessary. Methods
Patient’s selection and study population Statistical analysis All patients who underwent LT at Beaujon Hospital for Qualitative variables were expressed as number (perHCC within the Milan criteria From 1999 to 2009 and centage), and quantitative data as mean±standard deviasurvived at least 3 months after LT were included in the study. Data of the patients were retrospectively collected tion (SD). Overall survival was defined as time from surfrom their clinical files. The endpoint was HCC recurrence gery to death (excluding 90-day postoperative mortality). Disease-free survival was defined as time from surgery after LT and all factors were associated with recurrence. to the first recorded evidence of recurrence. Cumulative overall survival and disease-free survival rates were deDiagnostic modalities termined using the Kaplan-Meier method, and bivariate HCC diagnosis was based on two imaging studies in- analysis of survival was performed using the log-rank cluding triple-phase computed tomography scan and/or test. Significance was considered at the P value of 0.05. magnetic resonance imaging showing both early hyper- All analyses were performed with the GraphPad Prism® enhancement and delayed hypo-enhancement, in accor- 5.0c for Mac OS X (GraphPad Software, Inc., USA). dance with the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines of Management of Hepatocellular Carcinoma.[10] Patients with lesions Results within the Milan criteria had a solitary liver nodule not exceeding 5 cm in diameter, or 2 or 3 tumors not exceeding Among the 851 patients who underwent LT in our unit 3 cm in diameter, without detectable vascular invasion.[3] between 1999 and 2009, 258 (30.3%) had HCC on chronic Patients underwent regular ultrasound scan every 3-month liver disease and 218 (84.5%) had lesions within the Milan criteria before LT. Of these patients, 179 survived more to check that they remained within the Milan criteria. than 3 months and comprised the study population. Morphological evaluation before LT revealed that Pathological variables 96 (53.6%) patients had a single nodule with a mean Tumor size, number, differentiation grade, vascular diameter of 23.2±9.3 mm (range 30-50) and 72 had 2 or invasion, and satellite nodules were analyzed systematical3 nodules with a mean of 1.5±0.7 nodules each patient. ly. Vascular invasion was identified either as macroscopic, Demographic data, etiology of underlying liver disease when vessel invasion was visible on gross examination, or and MELD score are shown in Table 1. In this series, 129 as microscopic, when it was visible only under micros(72.1%) patients received bridging therapy including copy. Satellite nodules were defined as tumors ≤ 2 cm in transarterial chemoembolization (45 patients), percusize and located at ≤2 cm from the main tumor. Cholantaneous ethanol injection (14), radiofrequency ablation giocarcinoma differentiation (CC component) was re(55), and liver resection (54). Thirty-nine patients reported when present. Combined HCC-CC was diagnosed ceived two or more of these treatments in combination according to histological findings of both tumor types. before LT. The mean duration on the waiting list was 5.7 ± 5.3 months with no significant difference between the Immunosuppression groups with and without bridging therapy (6.1±5.2 vs A triple immunosuppressive regimen consisting of 4.7 ±5.5 months, respectively). mycophenolate mofetil, tacrolimus and steroids has been LT was performed using full grafts in 139 (77.7%) routinely used since 1999. In the present study, patients patients and partial grafts in 40 (22.3%), including grafts were free of steroids at 4-month post-LT, and no patients from living donors (23 patients) and from split procewere subjected to systematic mammalian target of rapa- dures (17). Pathological examination of the explanted mycin inhibitors. liver showed that 132 (73.7%) patients remained within the Milan criteria. Among the 47 patients beyond the Post-LT follow-up Milan criteria histologically, 15 had a tumor size >50 mm Follow-up included liver function tests, serum AFP and 23 had 4 nodules or more, and 9 patients had 2 or 3 and ultrasound examination every 3 months. Elevation nodules, with one nodule >30 mm. Ten patients (5.6%) 148 • Hepatobiliary Pancreat Dis Int，Vol 15，No 2 • April 15，2016 • www.hbpdint.com
HCC recurrence after liver transplantation
Table 1. Characteristics of the 179 patients who underwent LT for HCC within the Milan criteria (n, %) Demographics Male gender Age (yr) BMI (kg/m2) MELD score Etiology Alcohol HCV HBV HCV+HBV Other etiology F4 fibrosis F3 fibrosis Histological characteristics of the explanted liver Number of nodules 0 1 2 3 ≥4 Diameter of the largest nodule (mm) Complete necrosis Microvascular invasion Satellite nodules Differentiation Well Moderate Poor Cholangiocarcinoma component
Data 159 (88.8) 54.0±7.7 26.5±4.6 14.0±6.5 56 (31.3) 69 (38.5) 31 (17.3) 4 (2.2) 19 (10.6) 162 (90.5) 16 (8.9) 1.9±1.5 16 (8.9) 80 (44.7) 34 (19.0) 24 (14.0) 25 (13.9) 25.8±14.8 21 (11.7) 52 (29.1) 44 (24.6) 112 (62.6) 61 (34.1) 6 (3.4) 10 (5.6)
Table 2. Bivariate analysis of factors associated with HCC recurrence after LT Variables >1 nodule (n=83) HCV infection (n=73) HBV infection (n=35) Bridging therapy (n=129) AFP >400 ng/mL (n=12) Satellite nodules (n=44) Microvascular invasion (n=52) Poor differentiation (n=6) Cholangiocarcinoma component (n=10)
P value (log-rank test) 0.499 0.877 0.498 0.218 0.003 0.010 0.013 0.007 0.002
showed an additional CC component. The patients were followed up for 65.0±34.8 months. The overall 1-, 3- and 5-year survival rates were 86%, 75% and 71%, respectively. HCC recurrence was observed within a delay of 19±22 months in 11 (6.1%) patients. No patients had HCC recurrence within 3 months post-LT. HCC recurrence led to death in all patients with a mean delay between recurrence diagnosis and death of 6.7±5.0 months. All recurrences were multifocal ei-
Fig. Recurrence rate decreased according to prognostic factors.
ther with pulmonary, lymph nodes or bone involvement. HCC recurrence was observed in 5 (10.6%) of the 47 patients beyond the Milan criteria histologically as compared with 6 (4.5%) of the 132 patients within the Milan criteria histologically (P=0.160). The results of bivariate analysis of factors associated with HCC recurrence are shown in Table 2. Serum AFP level >400 ng/mL, satellite nodules, poor differentiation, microvascular invasion and CC component were associated with HCC recurrence after LT. The recurrence rate of HCC decreased from 6.1% to 3.1% when all prognostic factors identified either by liver biopsy or liver resection were ruled out (Fig.). In patients with adverse prognostic factors, those who underwent liver resection as a bridge to LT seemed to have better outcomes: two patients with a CC component had neither residual tumor in the explanted liver nor recurrence, and in eight patients with AFP >400 ng/mL, one experienced HCC recurrence.
Discussion This very restrictive approach we used could be theoretically interpreted as the most reasonable one in restricting organ waste and improving the accurate use.[10] In this study, we focused on selection of patients within the pre- LT Milan criteria which represent the most consensual guidelines.[11] HCC patients can be “favored” by allocation scores,[12] and the identification of a population subgroup that would benefit the most from LT without recurrence remains a cornerstone. In this setting, Hwang et al[13] proposed a “superselection category” of HCC patients with a recurrence rate of 1.3% at 10 years. The selection was based on four criteria: one or two tumor(s), size <2 cm, and AFP <200 ng/mL. In the present study, we chose a cut-off value of 400 ng/mL for AFP levels, as it was reported by Merani et al[14] that the last pre-LT AFP level <400 ng/mL independently predicted the survival. In another study, Hameed et al[15] focused on selection of HCC patients for LT. They found that, by choosing a threshold of AFP >400 ng/mL,
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9% of the patients would not be considered for LT, with a reduction of HCC recurrence by 26% in the transplanted patients. In patients with AFP >400 ng/mL and a reduction of HCC recurrence by 50%, 28% could be excluded from the LT program. This study has several limitations. First, the low number of patients with HCC recurrence for each variable did not allow us to perform a Cox multiple regression analysis.[16] Second, complete histology was not obtained in the pre-LT period. Adverse histological factors can be assessed by pre-LT biopsy or bridging liver resection. Bridging liver resection has several advantages: decreasing the risk of dropout on the waiting list,[17, 18] downstaging the tumor, and providing an accurate histological assessment. Our previous studies[19, 20] showed the safety and feasibility of partial liver resection before LT, which allowed selection of patients and could reduce the effect of adverse histological factors such as high AFP levels and the presence of CC component as demonstrated in the present study. Resected specimens provide information on tumor grade and vascular invasion.[21] If an HCC patient is assigned to have radiofrequency ablation while on the waiting list or as a down-staging treatment, a biopsy can be easily performed at the same time. Hence pre-LT biopsy could be useful in the selection of HCC patients for LT, even outside of the context of liver resection or radiofrequency ablation. Until now, HCC biopsy is mostly useful for the assessment of tumor differentiation,[21] even if it is not always representative of overall tumor burden.[22] However, other markers can be used to assess microvascular invasion or biological aggressiveness, such as keratin 19,[23] PIVKA-II,[24] and histone H4.[25] Recently we found that pre-LT tumor biopsy did not negatively influence the oncologic course of HCC patients eligible for LT.[26] Combined HCC-CC, also known as mixed HCC-CC, is a rare (incidence of primary liver cancer ranges from 0.87% to 4.7%) but increasingly recognized primary malignant neoplasm in the liver.[27-29] No significant differences have been found in etiologic risk factors between HCC-CC and HCC patients.[30] Imaging studies of combined HCC-CC depend on whether HCC or CC is a predominant component. Classic computed tomography image of combined HCC-CC has been characterized by early hypo-enhancement in the periphery and delayed enhancement in the center of the mass.[31] Determination of CC component could be improved by the evaluation of a delayed phase at magnetic resonance imaging showing the absence of contrast washout after a progressive arterial uptake.[32] Nevertheless, preoperative characterization remains challenging, enlightening both better accuracy of imaging findings and the key role of preoperative tumor biopsy or resection. As it was recently
published, once the diagnosis of HCC-CC is obtained by biopsy or resection, these poor prognosis patients should be excluded from the transplant program.[33] This proposed strategy of selecting HCC patients based more on histological criteria than on radiological findings can allow us to eliminate candidates within the Milan criteria, who are at the highest risk of recurrence, underlining the very important role of pre-LT biopsy and/or resection of both tumor and parenchyma. However, this strategy would certainly exclude some patients who have benefited from LT. Strategies aiming at transplant benefit, i.e. selection of patients whose difference in survival with LT with respect to other treatment is maximal, should actually be pursued for a major equity. Another benefit in grafts attribution strategies would be to adapt the timing of LT to the histological results of a prior liver resection for HCC. Patients with all good histological prognostic factors could be enlisted at the time of recurrence, whereas those with limited poor histological prognostic factors should be considered de principe for LT.[34] When too many factors associated with recurrence are present at the time of resection (AFP >400 ng/mL, CC component, poor differentiation, microvascular invasion, satellite nodules), these patients should definitely be excluded from the transplant program. In conclusion, decreasing post-LT recurrence rate towards zero is a hope in HCC patients within the Milan criteria. In order to achieve this theoretical goal, (i) patients with high AFP levels above 400 ng/mL should not be considered for LT, and (ii) pre-histological assessment by liver biopsy or liver resection would allow us to rule out poorly differentiated tumors, microvascular invasion, and CC component. Liver resection before LT could down-stage the tumor, provide important data about histological factors associated with post-transplant HCC recurrence, and thus help to select a subgroup population with a very-low potential recurrence rate. Contributors: Durand F and BJ proposed the study and revised manuscript. IS collected and analyzed data and wrote the first draft. BL revised the manuscript and submission. FC participated in the analysis and first draft. Dondéro F collected data and revised manuscript. BL is the guarantor. Funding: None. Ethical approval: This study was approved by the Ethics Committee of Beaujon Hospital. Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
References 1 Samuel D, Colombo M, El-Serag H, Sobesky R, Heaton N. Toward optimizing the indications for orthotopic liver trans-
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plantation in hepatocellular carcinoma. Liver Transpl 2011;17: S6-S13. 2 Mazzaferro V, Bhoori S, Sposito C, Bongini M, Langer M, Miceli R, et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl 2011;17:S44-S57. 3 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;334:693-699. 4 Duffy JP, Vardanian A, Benjamin E, Watson M, Farmer DG, Ghobrial RM, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA. Ann Surg 2007;246:502-511. 5 Duvoux C, Roudot-Thoraval F, Decaens T, Pessione F, Badran H, Piardi T, et al. Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria. Gastroenterology 2012;143:986-994. 6 Vibert E, Azoulay D, Hoti E, Iacopinelli S, Samuel D, Salloum C, et al. Progression of alphafetoprotein before liver transplantation for hepatocellular carcinoma in cirrhotic patients: a critical factor. Am J Transplant 2010;10:129-137. 7 DuBay D, Sandroussi C, Sandhu L, Cleary S, Guba M, Cattral MS, et al. Liver transplantation for advanced hepatocellular carcinoma using poor tumor differentiation on biopsy as an exclusion criterion. Ann Surg 2011;253:166-172. 8 Mazzaferro V, Chun YS, Poon RT, Schwartz ME, Yao FY, Marsh JW, et al. Liver transplantation for hepatocellular carcinoma. Ann Surg Oncol 2008;15:1001-1007. 9 Nakashima Y, Nakashima O, Tanaka M, Okuda K, Nakashima M, Kojiro M. Portal vein invasion and intrahepatic micrometastasis in small hepatocellular carcinoma by gross type. Hepatol Res 2003;26:142-147. 10 Neuberger J. Liver allocation for patients with hepatocellular carcinoma. Liver Transpl 2010;16:249-251. 11 Bruix J, Sherman M; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005;42:1208-1236. 12 Ioannou GN, Perkins JD, Carithers RL Jr. Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and predictors of survival. Gastroenterology 2008;134:1342-1351. 13 Hwang S, Ahn CS, Kim KH, Moon DB, Ha TY, Song GW, et al. Super-selection of a subgroup of hepatocellular carcinoma patients at minimal risk of recurrence for liver transplantation. J Gastrointest Surg 2011;15:971-981. 14 Merani S, Majno P, Kneteman NM, Berney T, Morel P, Mentha G, et al. The impact of waiting list alpha-fetoprotein changes on the outcome of liver transplant for hepatocellular carcinoma. J Hepatol 2011;55:814-819. 15 Hameed B, Mehta N, Sapisochin G, Roberts JP, Yao FY. Alphafetoprotein level >1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria. Liver Transpl 2014;20:945-951. 16 Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 1996;49:1373-1379. 17 Belghiti J, Carr BI, Greig PD, Lencioni R, Poon RT. Treatment before liver transplantation for HCC. Ann Surg Oncol 2008;15:993-1000. 18 Schwartz M, Roayaie S, Uva P. Treatment of HCC in patients awaiting liver transplantation. Am J Transplant 2007;7:1875-1881.
19 Belghiti J, Cortes A, Abdalla EK, Régimbeau JM, Prakash K, Durand F, et al. Resection prior to liver transplantation for hepatocellular carcinoma. Ann Surg 2003;238:885-893. 20 Fuks D, Dokmak S, Paradis V, Diouf M, Durand F, Belghiti J. Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case of recurrence: an intentionto-treat analysis. Hepatology 2012;55:132-140. 21 Durand F, Belghiti J, Paradis V. Liver transplantation for hepatocellular carcinoma: role of biopsy. Liver Transpl 2007;13: S17-S23. 22 Young RS, Aldiwani M, Hakeem AR, Nair A, Guthrie A, Wyatt J, et al. Pre-liver transplant biopsy in hepatocellular carcinoma: a potential criterion for exclusion from transplantation? HPB (Oxford) 2013;15:418-427. 23 van Malenstein H, Komuta M, Verslype C, Vandecaveye V, Van Calster B, Topal B, et al. Histology obtained by needle biopsy gives additional information on the prognosis of hepatocellular carcinoma. Hepatol Res 2012;42:990-998. 24 Poté N, Cauchy F, Albuquerque M, Voitot H, Belghiti J, Castera L, et al. Performance of PIVKA-II for early hepatocellular carcinoma diagnosis and prediction of microvascular invasion. J Hepatol 2015;62:848-854. 25 Poté N, Alexandrov T, Le Faouder J, Laouirem S, Léger T, Mebarki M, et al. Imaging mass spectrometry reveals modified forms of histone H4 as new biomarkers of microvascular invasion in hepatocellular carcinomas. Hepatology 2013;58:983-994. 26 Fuks D, Cauchy F, Fusco G, Paradis V, Durand F, Belghiti J. Preoperative tumour biopsy does not affect the oncologic course of patients with transplantable HCC. J Hepatol 2014;61:589-593. 27 Wang J, Wang F, Kessinger A. Outcome of combined hepatocellular and cholangiocarcinoma of the liver. J Oncol 2010;2010. pii: 917356. 28 Lee WS, Lee KW, Heo JS, Kim SJ, Choi SH, Kim YI, et al. Comparison of combined hepatocellular and cholangiocarcinoma with hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Surg Today 2006;36:892-897. 29 Yeh MM. Pathology of combined hepatocellular-cholangiocarcinoma. J Gastroenterol Hepatol 2010;25:1485-1492. 30 Chantajitr S, Wilasrusmee C, Lertsitichai P, Phromsopha N. Combined hepatocellular and cholangiocarcinoma: clinical features and prognostic study in a Thai population. J Hepatobiliary Pancreat Surg 2006;13:537-542. 31 Aoki K, Takayasu K, Kawano T, Muramatsu Y, Moriyama N, Wakao F, et al. Combined hepatocellular carcinoma and cholangiocarcinoma: clinical features and computed tomographic findings. Hepatology 1993;18:1090-1095. 32 Rimola J, Forner A, Reig M, Vilana R, de Lope CR, Ayuso C, et al. Cholangiocarcinoma in cirrhosis: absence of contrast washout in delayed phases by magnetic resonance imaging avoids misdiagnosis of hepatocellular carcinoma. Hepatology 2009;50:791-798. 33 Sapisochin G, Fidelman N, Roberts JP, Yao FY. Mixed hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma in patients undergoing transplantation for hepatocellular carcinoma. Liver Transpl 2011;17:934-942. 34 Tribillon E, Barbier L, Goumard C, Irtan S, Perdigao-Cotta F, Durand F, et al. When Should We Propose Liver Transplant After Resection of Hepatocellular Carcinoma? A Comparison of Salvage and De Principe Strategies. J Gastrointest Surg 2016;20:66-76. Received June 4, 2015 Accepted after revision November 24, 2015
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Liver transplantation for hepatocellular carcinoma: is zero recurrence theoretically possible? Sabine Irtan, Louise Barbier, Claire Francoz, Federica Dondéro, François Durand and Jacques Belghiti Clichy, France
BACKGROUND: Hepatocellular carcinoma (HCC) recurrence KEY WORDS: hepatocellular carcinoma; remains a key issue after liver transplantation. This study liver transplantation; aimed to determine a subgroup of HCC patients within the neoplasm recurrence; Milan criteria who could achieve a theoretical goal of zero resurvival rate currence rates after liver transplantation. METHODS: Between 1999 and 2009, 179 patients who received liver transplantation for HCC within the Milan criteria were retrospectively included. Analysis of the factors associated with HCC recurrence was performed to determine the subgroup of patients at the lowest risk of recurrence. RESULTS: Seventy-two percent of the patients received a bridging therapy, including 54 liver resections. Eleven (6.1%) patients recurred within a delay of 19±22 months and ultimately died. Factors associated with recurrence were serum alpha-fetoprotein level >400 ng/mL, satellite nodules, poor differentiation, microvascular invasion and cholangiocarcinoma component. Recurrence rates decreased from 6.1% to 3.1% in patients without any of these factors. CONCLUSIONS: Among HCC patients within the Milan criteria, selecting patients with factors based on histology would allow tending towards zero recurrence, and prior histological assessment by liver biopsy or resection may be essential to rule out poorly differentiated tumors, microvascular invasion, and cholangiocarcinoma component. (Hepatobiliary Pancreat Dis Int 2016;15:147-151)
Author Affiliations: Department of Hepato-Pancreato-Biliary Surgery (Irtan S, Barbier L, Dondéro F and Belghiti J) and Department of Hepatology (Francoz C and Durand F), Beaujon Hospital, Assistance PubliqueHôpitaux de Paris, University Denis Diderot-Paris VII, Clichy, France Corresponding Author: Louise Barbier, MD, Department of HepatoPancreato-Biliary Surgery, Beaujon Hospital, 100 Boulevard du Général Leclerc, 92118 Clichy Cedex, France (Tel: +33-1-4087-5895; Fax: +33-14087-1724; Email: [email protected]) © 2016, Hepatobiliary Pancreat Dis Int. All rights reserved. doi: 10.1016/S1499-3872(16)60069-3 Published online February 2, 2016.
Introduction
L
iver transplantation (LT) remains the best treatment of early hepatocellular carcinoma (HCC) developed on chronic liver disease. However, results are hampered by the long-lasting imbalance between an increasing number of candidates and graft shortage.[1] The unsatisfactory initial results of LT for clinically advanced HCC, together with the observation that small HCCs incidentally detected during surgery have an extremely low risk of post-LT recurrence, led to propose strict selection criteria.[2, 3] In this setting, the Milan criteria (single tumor ≤5 cm or 2-3 tumors ≤3 cm, in the absence of macroscopic vascular invasion) were adopted as guidelines for LT with the aim to achieve a 5-year overall survival rate of 70% and a recurrence rate of below 15%.[3] Increasing experience showed that some HCC patients beyond the Milan criteria, without vascular invasion or poorly differentiated HCC, demonstrated acceptable rates of survival and recurrence.[4] Several studies[5, 6] showed that high or rapidly increasing alpha-fetoprotein (AFP) levels were associated with increased recurrence. A study from a Toronto team showed that patients beyond the Milan criteria with AFP level >400 ng/mL and well differentiated HCC could achieve excellent results after LT.[7] On the other hand, even restricting LT for patients within the Milan criteria fails in completely ruling out post-LT for HCC recurrence[8] since some small HCCs have aggressive features such as poorly differentiated grade or vascular invasion.[9] In a context of graft shortage, a policy to select HCC candidates with post-LT outcomes similar to non-HCC recipients, while eliminating recurrence risk factors, should theoretically be considered. The
Hepatobiliary Pancreat Dis Int，Vol 15，No 2 • April 15，2016 • www.hbpdint.com • 147
Hepatobiliary & Pancreatic Diseases International
aim of this study was therefore to determine a subgroup of AFP and/or presence of nodule at ultrasound led to of patients within the Milan criteria, which could theo- perform triple-phase computed tomography or magretically achieve a zero recurrence rate after LT. netic resonance imaging. HCC recurrence was defined as appearance of a new lesion with radiological features of HCC. Additional imaging techniques (bone scan, magnetic resonance imaging) were used if necessary. Methods
Patient’s selection and study population Statistical analysis All patients who underwent LT at Beaujon Hospital for Qualitative variables were expressed as number (perHCC within the Milan criteria From 1999 to 2009 and centage), and quantitative data as mean±standard deviasurvived at least 3 months after LT were included in the study. Data of the patients were retrospectively collected tion (SD). Overall survival was defined as time from surfrom their clinical files. The endpoint was HCC recurrence gery to death (excluding 90-day postoperative mortality). Disease-free survival was defined as time from surgery after LT and all factors were associated with recurrence. to the first recorded evidence of recurrence. Cumulative overall survival and disease-free survival rates were deDiagnostic modalities termined using the Kaplan-Meier method, and bivariate HCC diagnosis was based on two imaging studies in- analysis of survival was performed using the log-rank cluding triple-phase computed tomography scan and/or test. Significance was considered at the P value of 0.05. magnetic resonance imaging showing both early hyper- All analyses were performed with the GraphPad Prism® enhancement and delayed hypo-enhancement, in accor- 5.0c for Mac OS X (GraphPad Software, Inc., USA). dance with the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines of Management of Hepatocellular Carcinoma.[10] Patients with lesions Results within the Milan criteria had a solitary liver nodule not exceeding 5 cm in diameter, or 2 or 3 tumors not exceeding Among the 851 patients who underwent LT in our unit 3 cm in diameter, without detectable vascular invasion.[3] between 1999 and 2009, 258 (30.3%) had HCC on chronic Patients underwent regular ultrasound scan every 3-month liver disease and 218 (84.5%) had lesions within the Milan criteria before LT. Of these patients, 179 survived more to check that they remained within the Milan criteria. than 3 months and comprised the study population. Morphological evaluation before LT revealed that Pathological variables 96 (53.6%) patients had a single nodule with a mean Tumor size, number, differentiation grade, vascular diameter of 23.2±9.3 mm (range 30-50) and 72 had 2 or invasion, and satellite nodules were analyzed systematical3 nodules with a mean of 1.5±0.7 nodules each patient. ly. Vascular invasion was identified either as macroscopic, Demographic data, etiology of underlying liver disease when vessel invasion was visible on gross examination, or and MELD score are shown in Table 1. In this series, 129 as microscopic, when it was visible only under micros(72.1%) patients received bridging therapy including copy. Satellite nodules were defined as tumors ≤ 2 cm in transarterial chemoembolization (45 patients), percusize and located at ≤2 cm from the main tumor. Cholantaneous ethanol injection (14), radiofrequency ablation giocarcinoma differentiation (CC component) was re(55), and liver resection (54). Thirty-nine patients reported when present. Combined HCC-CC was diagnosed ceived two or more of these treatments in combination according to histological findings of both tumor types. before LT. The mean duration on the waiting list was 5.7 ± 5.3 months with no significant difference between the Immunosuppression groups with and without bridging therapy (6.1±5.2 vs A triple immunosuppressive regimen consisting of 4.7 ±5.5 months, respectively). mycophenolate mofetil, tacrolimus and steroids has been LT was performed using full grafts in 139 (77.7%) routinely used since 1999. In the present study, patients patients and partial grafts in 40 (22.3%), including grafts were free of steroids at 4-month post-LT, and no patients from living donors (23 patients) and from split procewere subjected to systematic mammalian target of rapa- dures (17). Pathological examination of the explanted mycin inhibitors. liver showed that 132 (73.7%) patients remained within the Milan criteria. Among the 47 patients beyond the Post-LT follow-up Milan criteria histologically, 15 had a tumor size >50 mm Follow-up included liver function tests, serum AFP and 23 had 4 nodules or more, and 9 patients had 2 or 3 and ultrasound examination every 3 months. Elevation nodules, with one nodule >30 mm. Ten patients (5.6%) 148 • Hepatobiliary Pancreat Dis Int，Vol 15，No 2 • April 15，2016 • www.hbpdint.com
HCC recurrence after liver transplantation
Table 1. Characteristics of the 179 patients who underwent LT for HCC within the Milan criteria (n, %) Demographics Male gender Age (yr) BMI (kg/m2) MELD score Etiology Alcohol HCV HBV HCV+HBV Other etiology F4 fibrosis F3 fibrosis Histological characteristics of the explanted liver Number of nodules 0 1 2 3 ≥4 Diameter of the largest nodule (mm) Complete necrosis Microvascular invasion Satellite nodules Differentiation Well Moderate Poor Cholangiocarcinoma component
Data 159 (88.8) 54.0±7.7 26.5±4.6 14.0±6.5 56 (31.3) 69 (38.5) 31 (17.3) 4 (2.2) 19 (10.6) 162 (90.5) 16 (8.9) 1.9±1.5 16 (8.9) 80 (44.7) 34 (19.0) 24 (14.0) 25 (13.9) 25.8±14.8 21 (11.7) 52 (29.1) 44 (24.6) 112 (62.6) 61 (34.1) 6 (3.4) 10 (5.6)
Table 2. Bivariate analysis of factors associated with HCC recurrence after LT Variables >1 nodule (n=83) HCV infection (n=73) HBV infection (n=35) Bridging therapy (n=129) AFP >400 ng/mL (n=12) Satellite nodules (n=44) Microvascular invasion (n=52) Poor differentiation (n=6) Cholangiocarcinoma component (n=10)
P value (log-rank test) 0.499 0.877 0.498 0.218 0.003 0.010 0.013 0.007 0.002
showed an additional CC component. The patients were followed up for 65.0±34.8 months. The overall 1-, 3- and 5-year survival rates were 86%, 75% and 71%, respectively. HCC recurrence was observed within a delay of 19±22 months in 11 (6.1%) patients. No patients had HCC recurrence within 3 months post-LT. HCC recurrence led to death in all patients with a mean delay between recurrence diagnosis and death of 6.7±5.0 months. All recurrences were multifocal ei-
Fig. Recurrence rate decreased according to prognostic factors.
ther with pulmonary, lymph nodes or bone involvement. HCC recurrence was observed in 5 (10.6%) of the 47 patients beyond the Milan criteria histologically as compared with 6 (4.5%) of the 132 patients within the Milan criteria histologically (P=0.160). The results of bivariate analysis of factors associated with HCC recurrence are shown in Table 2. Serum AFP level >400 ng/mL, satellite nodules, poor differentiation, microvascular invasion and CC component were associated with HCC recurrence after LT. The recurrence rate of HCC decreased from 6.1% to 3.1% when all prognostic factors identified either by liver biopsy or liver resection were ruled out (Fig.). In patients with adverse prognostic factors, those who underwent liver resection as a bridge to LT seemed to have better outcomes: two patients with a CC component had neither residual tumor in the explanted liver nor recurrence, and in eight patients with AFP >400 ng/mL, one experienced HCC recurrence.
Discussion This very restrictive approach we used could be theoretically interpreted as the most reasonable one in restricting organ waste and improving the accurate use.[10] In this study, we focused on selection of patients within the pre- LT Milan criteria which represent the most consensual guidelines.[11] HCC patients can be “favored” by allocation scores,[12] and the identification of a population subgroup that would benefit the most from LT without recurrence remains a cornerstone. In this setting, Hwang et al[13] proposed a “superselection category” of HCC patients with a recurrence rate of 1.3% at 10 years. The selection was based on four criteria: one or two tumor(s), size <2 cm, and AFP <200 ng/mL. In the present study, we chose a cut-off value of 400 ng/mL for AFP levels, as it was reported by Merani et al[14] that the last pre-LT AFP level <400 ng/mL independently predicted the survival. In another study, Hameed et al[15] focused on selection of HCC patients for LT. They found that, by choosing a threshold of AFP >400 ng/mL,
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9% of the patients would not be considered for LT, with a reduction of HCC recurrence by 26% in the transplanted patients. In patients with AFP >400 ng/mL and a reduction of HCC recurrence by 50%, 28% could be excluded from the LT program. This study has several limitations. First, the low number of patients with HCC recurrence for each variable did not allow us to perform a Cox multiple regression analysis.[16] Second, complete histology was not obtained in the pre-LT period. Adverse histological factors can be assessed by pre-LT biopsy or bridging liver resection. Bridging liver resection has several advantages: decreasing the risk of dropout on the waiting list,[17, 18] downstaging the tumor, and providing an accurate histological assessment. Our previous studies[19, 20] showed the safety and feasibility of partial liver resection before LT, which allowed selection of patients and could reduce the effect of adverse histological factors such as high AFP levels and the presence of CC component as demonstrated in the present study. Resected specimens provide information on tumor grade and vascular invasion.[21] If an HCC patient is assigned to have radiofrequency ablation while on the waiting list or as a down-staging treatment, a biopsy can be easily performed at the same time. Hence pre-LT biopsy could be useful in the selection of HCC patients for LT, even outside of the context of liver resection or radiofrequency ablation. Until now, HCC biopsy is mostly useful for the assessment of tumor differentiation,[21] even if it is not always representative of overall tumor burden.[22] However, other markers can be used to assess microvascular invasion or biological aggressiveness, such as keratin 19,[23] PIVKA-II,[24] and histone H4.[25] Recently we found that pre-LT tumor biopsy did not negatively influence the oncologic course of HCC patients eligible for LT.[26] Combined HCC-CC, also known as mixed HCC-CC, is a rare (incidence of primary liver cancer ranges from 0.87% to 4.7%) but increasingly recognized primary malignant neoplasm in the liver.[27-29] No significant differences have been found in etiologic risk factors between HCC-CC and HCC patients.[30] Imaging studies of combined HCC-CC depend on whether HCC or CC is a predominant component. Classic computed tomography image of combined HCC-CC has been characterized by early hypo-enhancement in the periphery and delayed enhancement in the center of the mass.[31] Determination of CC component could be improved by the evaluation of a delayed phase at magnetic resonance imaging showing the absence of contrast washout after a progressive arterial uptake.[32] Nevertheless, preoperative characterization remains challenging, enlightening both better accuracy of imaging findings and the key role of preoperative tumor biopsy or resection. As it was recently
published, once the diagnosis of HCC-CC is obtained by biopsy or resection, these poor prognosis patients should be excluded from the transplant program.[33] This proposed strategy of selecting HCC patients based more on histological criteria than on radiological findings can allow us to eliminate candidates within the Milan criteria, who are at the highest risk of recurrence, underlining the very important role of pre-LT biopsy and/or resection of both tumor and parenchyma. However, this strategy would certainly exclude some patients who have benefited from LT. Strategies aiming at transplant benefit, i.e. selection of patients whose difference in survival with LT with respect to other treatment is maximal, should actually be pursued for a major equity. Another benefit in grafts attribution strategies would be to adapt the timing of LT to the histological results of a prior liver resection for HCC. Patients with all good histological prognostic factors could be enlisted at the time of recurrence, whereas those with limited poor histological prognostic factors should be considered de principe for LT.[34] When too many factors associated with recurrence are present at the time of resection (AFP >400 ng/mL, CC component, poor differentiation, microvascular invasion, satellite nodules), these patients should definitely be excluded from the transplant program. In conclusion, decreasing post-LT recurrence rate towards zero is a hope in HCC patients within the Milan criteria. In order to achieve this theoretical goal, (i) patients with high AFP levels above 400 ng/mL should not be considered for LT, and (ii) pre-histological assessment by liver biopsy or liver resection would allow us to rule out poorly differentiated tumors, microvascular invasion, and CC component. Liver resection before LT could down-stage the tumor, provide important data about histological factors associated with post-transplant HCC recurrence, and thus help to select a subgroup population with a very-low potential recurrence rate. Contributors: Durand F and BJ proposed the study and revised manuscript. IS collected and analyzed data and wrote the first draft. BL revised the manuscript and submission. FC participated in the analysis and first draft. Dondéro F collected data and revised manuscript. BL is the guarantor. Funding: None. Ethical approval: This study was approved by the Ethics Committee of Beaujon Hospital. Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
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