Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA

OBJECTIVE: To assess the efficacy of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) and the impact of current staging criteria on long term survival. SUMMARY BACKGROUND DATA: HCC is becoming an increasingly common indication for OLT. Medicare approves OLT only for HCCs meeting the Milan criteria, thus limiting OLT for an expanding pool of potential liver recipients. We analyzed our experience with OLT for HCC to determine if expansion of criteria for OLT for HCC is warranted. METHODS:: All patients undergoing OLT for HCC from 1984 to 2006 were evaluated. Outcomes were compared for patients who met Milan criteria (single tumor < opr =5 cm, maximum of 3 total tumors with none >3 cm), University of California, San Francisco (UCSF) criteria (single tumor <6.5 cm, maximum of 3 total tumors with none >4.5 cm, and cumulative tumor size <8 cm), or exceeded UCSF criteria. RESULTS: A total of 467 transplants were performed for HCC. At mean follow up of 6.6 +/- 0.9 years, recurrence rate was 21.2%, and overall 1, 3, and 5-year survival was 82%, 65%, and 52%, respectively. Patients meeting Milan criteria had similar 5-year post-transplant survival to patients meeting UCSF criteria by preoperative imaging (79% vs. 64%; P = 0.061) and explant pathology (86% vs. 71%; P = 0.057). Survival for patients with tumors beyond UCSF criteria was significantly lower and was below 50% at 5 years. Multivariate analysis showed that tumor number (P < 0.001), lymphovascular invasion (P < 0.001), and poor differentiation (P = 0.002) independently predicted poor survival. CONCLUSIONS: This largest single institution experience with OLT for HCC demonstrates prolonged survival after liver transplantation for tumors beyond Milan criteria but within UCSF criteria, both when classified by preoperative imaging and by explant pathology. Measured expansion of OLT criteria is justified for tumors not exceeding the UCSF criteria.     

Liver transplantation for hepatocellular carcinoma: Comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria

We previously proposed modified staging criteria for predicting acceptable outcome after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). These were solitary tumor ≤6.5 cm, or three or fewer nodules with the largest lesion ≤4.5 cm and total tumor diameter ≤8 cm, without gross vascular invasion (University of California, San Francisco [UCSF] criteria). In this study, we further evaluated the performance of the Milan criteria (solitary tumor ≤5 cm, or three or fewer lesions none >3 cm), the UCSF criteria, and the Pittsburgh modified tumor-node-metastasis (TNM) criteria. Pathologic HCC staging according to each set of criteria was performed in 70 patients. The difference in survival when comparing 24 patients with HCC exceeding Milan criteria versus 46 patients meeting Milan criteria did not reach statistical significance (HR, 2.0; P = .12). Using our definition for acceptable 2-year survival to be ≥70%, the 14 patients (20%) meeting UCSF criteria but exceeding Milan criteria had a 2-year survival of 86% (95% CI, 54% to 96%). Survival for Pittsburgh stage I, II, and IIIA patients as a group was significantly better than for stages IIIB and IVA patients combined (HR, 4.2; P = .007), and similar to survival for patients meeting UCSF criteria. Advanced tumor exceeding UCSF criteria served reasonably well as a surrogate marker for poorly differentiated grade and microvascular invasion. In conclusion, our analyses suggest that UCSF criteria better predict acceptable posttransplant outcome than Milan criteria. UCSF criteria confer a different advantage over Pittsburgh criteria, which require information on microvascular invasion that is difficult to ascertain preoperatively without the attendant risk of biopsy. (Liver Transpl 2002;8:765-774.)     

Liver Transplantation for Hepatocellular Carcinoma: Results of a Multicenter Study With Common Priorization Criteria

Objective

To evaluate the results of liver transplantation (OLT) performed for hepatocellular carcinoma (HCC) among a multicenter cohort of patients with predefined common inclusion and priorization criteria.

Patients and Methods

Over a 5-year period (January 2002-December 2006), 199 HCC patients underwent OLT in four centers in Andalusia. The morphological (Milan) inclusion criteria were priorized in two consecutive periods, according to the Model for End-stage Liver Disease score: group I, 53 patients (HCC < 2 cm = 24 points; ≥ 2 cm or multinodular = 29 points) and group II, 146 cases (HCC < 3 cm without priorization; HCC ≥ 3 cm or multinodular = 18 points).

Results

Among the 199 HCCs, 186 (93.5%) subjects were transplanted and 13 (6.5%) were excluded. There were 18 cases (9.7%) where the diagnosis was incidental and 168 were known HCC cases; 144 (85.7%) complied with the Milan criteria (Milan+); 24 (14.3%) exceeded there criteria (Milan−). According to preoperative imaging, the number of nodules and tumor mean sizes among the excluded—Milan+ and Milan− groups—were 1.8/5.3 cm, 1.4/3.5 cm, and 2.3/6.7 cm, respectively (P < .001). Percutaneous treatment during listing was delivered to 55% of the excluded cases: 49% of Milan+ and 96% of Milan−. The median time on the list was 88 days for known HCC (53 days for group I, and 97 days for group II), and 172 days for the incidental HCCs. Staging (pTNM) was correct in 64% of cases: 23% were understaged and 13% were overstaged. Overall mortality within the first 90 days was 9%, and transplant patient survival at 5 years was 61%. No differences were observed in survival rates between both study periods, although there were differences between the Milan+ (65%) and Milan− (23%) groups (P < .04). In addition, the difference in the recurrence rates was also significant between the Milan+ (7%), Milan− (24%), and the incidental (25%) groups (P < .02).

Conclusions

A common priorization policy of HCC for OLT based on morphological criteria results in a low exclusion rate on the waiting lists (6.5%). The Milan criteria are still a good cutoff to stratify the risk of recurrence, despite preoperative tumor staging being correct in only two-thirds of cases.     

Downstaging prior to liver transplantation for hepatocellular carcinoma: advisable but at the price of an increased risk of cancer recurrence – a retrospective study

The use of downstaging prior to liver transplantation for hepatocellular carcinoma (HCC) still needs refinement. This study included patients with HCC listed for transplantation according to the Total Tumour Volume (TTV) ≤115 cm³ and alpha fetoprotein (AFP) ≤400 ng/ml criteria, with and without previous downstaging. Overall, 455 patients were listed, and 286 transplanted. Post‐transplant follow‐up was 38.5 ± 1.7 months. Patients downstaged to TTV115/AFP400 (n = 29) demonstrated similar disease‐free survivals (DFS, 74% vs. 80% at 5 years, P = 0.949), but a trend to more recurrences (14% vs. 5.8%, P = 0.10) than those always within TTV115/AFP400 (n = 257). Similarly, patients downstaged to Milan criteria (n = 80) demonstrated similar DFS (76% vs. 86% at 5 years, P = 0.258), but more recurrences (11% vs. 1.7%, P = 0.001) than those always within Milan (n = 177). Among patients downstaged to Milan, those originally beyond TTV115/AFP400 (n = 27) had similar outcomes as those originally beyond Milan, but within TTV115/AFP400 (n = 53). However, the likelihood of being within Milan at transplant was lower for patients with more advanced original HCCs (P < 0.0001). Overall, despite an expected increase in post‐transplant HCC recurrence, similar survivals can be achieved with and without downstaging, using the TTV115/AFP400 transplantation criteria, and including patients with advanced original HCCs. Downstaging should continue to be performed.     

Expanded living‐donor liver transplantation criteria for patients with hepatocellular carcinoma based on the Japanese nationwide survey: the 5‐5‐500 rule ‐ a retrospective study

Expansion of the liver transplantation indication criteria for patients with hepatocellular carcinoma (HCC) has long been debated. Here we propose new, expanded living‐donor liver transplantation (LDLT) criteria for HCC patients based on a retrospective data analysis of the Japanese nationwide survey. A total of 965 HCC patients undergoing LDLT were included, 301 (31%) of whom were beyond the Milan criteria. Here, we applied the Greenwood formula to investigate new criteria enabling the maximal enrollment of candidates while securing a 5‐year recurrence rate (95% upper confidence limit) below 10% by examining various combinations of tumor numbers and serum alpha‐fetoprotein values, and maintaining the maximal nodule diameter at 5 cm. Finally, new expanded criteria for LDLT candidates with HCC, the 5‐5‐500 rule (nodule size ≤5 cm in diameter, nodule number ≤5, and alfa‐fetoprotein value ≤500 ng/ml), were established as a new regulation with a 95% confidence interval of a 5‐year recurrence rate of 7.3% (5.2–9.3) and a 19% increase in the number of eligible patients. In addition, the 5‐5‐500 rule could identify patients at high risk of recurrence, among those within and beyond the Milan criteria. In conclusion, the new criteria – the 5‐5‐500 rule – might provide rational expansion for LDLT candidates with HCC.     

Liver Transplantation for Hepatocellular Carcinoma: Beyond the Milan Criteria

Liver transplantation represents a cornerstone in the management of early‐stage hepatocellular carcinoma (HCC). Expansion beyond the Milan criteria for liver transplantation (1 lesion ≤ 5 cm, or 2 to 3 lesions each ≤ 3 cm) remains controversial. This review covers several key areas: (1) Recent developments and published data on expanded criteria for deceased donor and live‐donor liver transplantation, with emphasis on criteria that have been applied to preoperative imaging. (2) Independent testing of expanded criteria, where published data are largely limited to the proposed University of California, San Francisco criteria (1 lesion ≤ 6.5 cm, 2–3 lesions each ≤ 4.5 cm with total tumor diameter ≤ 8 cm). (3) Response to loco‐regional therapy and tumor downstaging. (4) The fundamental questions and answers in resolving the controversy over expanded criteria. The key issue pertains to whether acceptable outcome can be achieved on a broader scale beyond single center experience, which appears to support modest expansion beyond the Milan criteria. The foundation of the debate over expanded criteria may rest upon what the transplant community would consider to be the acceptable threshold for patient survival using expanded criteria, without causing significant harm to other transplant candidates without HCC.     

Can we expand the Milan criteria for hepatocellular carcinoma in living donor liver transplantation?

INTRODUCTION: The Milan criteria, namely, tumors 5 cm or less in diameter in patients with single hepatocellular carcinoma (HCC), no more than 3 tumor nodules, and each 3 cm or less in diameter in patients with multiple tumors, are accepted for cadaveric liver allocation. However, in living donor liver transplantation (LDLT), graft donation may only depend on the donor's intention. The aim of this study was to elucidate the feasibility of Milan criteria in LDLT. MATERIALS AND METHODS: From January 2001 to December 2002, 46 cases of liver transplantation (LT) for HCC included 5 hospital mortalities and 3 cadaveric transplantations, all of which were excluded. We classified the patients into Group I cases that met the Milan criteria and Group II cases that did not meet the Milan criteria. The analyses examined tumor-related risk factors affecting recurrence and survival, such as tumor size, number of tumor nodules, and presence of microvascular and macrovascular invasion. RESULTS: Twenty-one cases belonged to Group I and 17 to Group II. There was no significant difference in the recurrence or survival rates between Groups I and II. The risk factors affecting recurrence were macrovascular invasion and tumor size (5 cm). The number of tumor nodules and microvascular invasion did not appear to affect recurrence. The risk factor affecting survival was macrovascular invasion. CONCLUSION: We suggest that in selected cases the Milan criteria could be extended to increase the number of tumor nodules as long as the HCC were small and did not macrovascular invasion.     

A single‐center retrospective analysis of liver transplantation on 255 patients with hepatocellular carcinoma

Wang Z‐X, Song S‐H, Teng F, Wang G‐H, Guo W‐Y, Shi X‐M, Ma J, Wu Y‐M, Ding G‐S, Fu Z‐R. A single‐center retrospective analysis of liver transplantation on 255 patients with hepatocellular carcinoma.
Clin Transplant 2010: 24: 752–757. © 2009 John Wiley & Sons A/S. Abstract: Background: Liver transplantation (LT) was advocated as a salvage treatment of choice for patients with unresectable hepatocellular carcinoma (HCC). This study was designed to assess the eligibility of LT criteria for patients with HCC and to analyze the factors influencing the recurrence of HCC following LT, aiming to further improve the efficacy of LT for patients with HCC. Methods: Clinical data of 255 patients with HCC who underwent LT between December 2001 and December 2007 at Shanghai Changzheng Hospital, China were retrospectively analyzed. Results: Among these cases, 75 patients were within the Milan criteria and 180 were beyond it; 110 patients were within the University of California, San Francisco (UCSF) criteria, while 145 were beyond it. The difference in overall survival rates was not only significant between the patients within and beyond the Milan criteria but also between patients within and beyond the UCSF criteria. Tumor‐node‐metastasis (TNM) staging, portal vein tumor thrombus (PVTT), and the pre‐operative alpha‐fetoprotein (AFP) level were independent risk factors affecting the overall survival and post‐operative recurrence‐free survival rates of patients with HCC. Pathological staging and pre‐operative local treatment of HCC had no obvious correlation with the post‐operative recurrence‐free survival rate. Conclusion: LT is an effective treatment modality for HCC. The UCSF criteria did not show better effectiveness than the Milan criteria. TNM staging, PVTT, and the pre‐operative AFP level are closely related to the recurrence of HCC following LT.     

Super-selection of a Subgroup of Hepatocellular Carcinoma Patients at Minimal Risk of Recurrence for Liver Transplantation

Background

A majority of patients with hepatocellular carcinoma (HCC) undergoing liver transplantation (LT) meet the Milan criteria, but these are still regarded as the narrowest criteria for transplantation. Prognostic analysis of incidentally detected HCC after LT suggests that a subgroup of HCC patients is at very low risk of recurrence. To determine the criteria defining this super-selection group, we retrospectively analyzed survival data of 593 adult living-donor LT recipients with HCC in the explanted liver

Discussion

Tumor features of incidental HCC in 38 patients not showing recurrence were analyzed. Of these patients, 34 (89.5%) each had ≤2 tumors and tumors ≤2.0 cm in size. Applying these criteria to 555 patients with pretransplant known HCC (pkHCC) allowed us to identify 79 patients with untreated pkHCCs ≤2.0 cm in size. To date, only two of these patients have shown recurrence, making the conditions for super-selection the presence of tumors ≤2.0 cm in size, ≤2 tumors, alpha-fetoprotein ≤200 ng/mL, and no pretransplant treatment. In 87 patients satisfying these criteria, the 10-year recurrence and survival rates were 1.3% and 92.1%, respectively. After excluding patients meeting these criteria, the 5-year recurrence rates in patients satisfying the Milan, University of California at San Francisco, and Asan criteria were increased by 2.9–4.0%. In conclusion, this super-selection or super-Milan category may be used for validation assessment of various indication criteria and for the development of cost-effective post-transplantation HCC surveillance protocols. Further studies should be followed for deceased-donor LT and patients who have undergone pretransplant treatment.     

Tumor biology and pre‐transplant locoregional treatments determine outcomes in patients with T3 hepatocellular carcinoma undergoing liver transplantation

Liver transplantation is the optimal treatment for patients with hepatocellular carcinoma (HCC) and cirrhosis. This study was conducted to determine the impact of pre‐transplant locoregional therapy (LRT) on HCC and our institution's experience with expansion to United Network of Organ Sharing Region 4 T3 (R4T3) criteria. Two hundred and twenty‐five patients with HCC (176 meeting Milan and 49 meeting R4T3 criteria) underwent liver transplantation from 2002 to 2008. Compared with the Milan criteria, HCCs in R4T3 criteria displayed less favorable biological features such as higher median alpha‐fetoprotein level (21.9 vs. 8.5 ng/mL, p = 0.01), larger tumor size, larger tumor number, and higher incidence of microvascular invasion (22% vs. 5%, p = 0.002). As a result, patients meeting Milan criteria had better five‐yr survival (79% vs. 69%, p = 0.03) and a trend toward lower HCC recurrence rates (5% vs. 13%, p = 0.05). Pre‐transplant LRT did not affect post‐transplant outcomes in patients meeting Milan criteria but did result in lower three‐yr HCC recurrence (7% vs. 75%, p < 0.001) and better three‐yr survival (p = 0.02) in patients meeting R4T3 criteria. Tumor biology and pre‐transplant LRT are important factors that determine the post‐transplant outcomes in patients with HCC who meet R4T3 criteria.     

A long‐term experience with expansion of Milan criteria for liver transplant recipients

The Milan criteria (MC) have historically determined eligibility for transplantation for hepatocellular carcinoma (HCC). The United Network for Organ Sharing (UNOS) Region 4 expanded the criteria for transplantation in HCC to include a single tumor ≤6 cm or up to 3 tumors with the largest diameter ≤5 cm and total additive diameter ≤9 cm (R4C). The aim of this study was to report the 10‐year outcomes of this expanded criteria compared to MC. Transplants performed for HCC in Region 4 between October 2007 and December 2016 were reviewed using the UNOS database. Recipients were categorized based on imaging findings at initial evaluation. A total of 2068 patients were included in the study. There was no significant difference in 10‐year patient survival between the groups (53% MC vs 48% R4C, P = .23). There was also no significant difference in recurrence‐free survival (54% MC vs 47% R4C, P = .15) or allograft survival (53% MC vs 48% R4C, P = .16). Finally, there was no significant difference in outcomes between the MC and R4C groups when stratifying patients by locoregional therapy. This study demonstrates promising data that the criteria for liver transplantation in HCC can be safely expanded to the R4C without compromising outcomes.     

Outcomes and recurrence of initially resectable hepatocellular carcinoma meeting milan criteria: Rationale for partial hepatectomy as first strategy

BACKGROUND: Partial hepatectomy and liver transplantation are considered curative treatments for small hepatocellular carcinoma (HCC) meeting the Milan criteria (solitary tumor <5 cm or up to 3 nodules <3 cm). This study was designed to clarify whether partial hepatectomy can be the first option in patients eligible for both treatments. STUDY DESIGN: All patients (n = 152) underwent curative surgical operation for primary HCC during 2000 to 2005 at our hospital. Eighty-seven patients met Milan criteria and the remaining 65 did not. Outcomes were examined according to Milan criteria. RESULTS: After partial hepatectomy, 3-year survival rate was 89.6% for the group that met Milan criteria, compared with 60.8% for the group that did not (p = 0.0044). Among patients with HCC who initially met the criteria, tumor recurrences were observed in 30 patients; 23 patients met criteria and 7 patients exceeded the criteria at first diagnosis of recurrence. Patients with recurrence within the criteria showed a higher 3-year survival rate compared with patients with recurrence exceeding the criteria (100% versus 19.8%; p < 0.0001). Analysis of clinicopathologic variables to predict mode of recurrence revealed tumor size (p < 0.0001) and lower histologic differentiation (p = 0.0326) as positive factors for recurrence exceeding Milan criteria. CONCLUSIONS: Our results suggest that it is an appropriate strategy to treat HCC patients who meet Milan criteria with partial hepatectomy. It should be noted that approximately one-tenth of patients who initially met Milan criteria experienced postoperative recurrence that exceeded the criteria.     

Influence of coexisting cirrhosis on outcomes after partial hepatic resection for hepatocellular carcinoma fulfilling the Milan criteria: an analysis of 293 patients

BACKGROUND: For patients with liver cirrhosis and hepatocellular carcinoma (HCC) satisfying the Milan criteria (single tumor < or =5 cm or 2 or 3 tumors < or =3 cm), orthotopic liver transplantation (OLT) is an effective treatment. Nevertheless, it remains controversial whether OLT is the best treatment strategy for patients with resectable HCC. METHODS: This study included 293 HCC patients (both with and without cirrhosis) oncologically satisfying the Milan criteria who underwent primary and curative liver resection between 1990 and 2003. RESULTS: There were 127 noncirrhotic, 129 Child-Pugh A cirrhotic, and 37 Child-Pugh B cirrhotic patients. Five-year survival rates in each population were 81%, 54%, and 28%, respectively. Coexisting cirrhosis, Child-Pugh classification, alpha-fetoprotein value, tumor burden, and vascular invasion by the tumor were identified as significant prognostic factors. Among these factors, coexisting cirrhosis was the most crucial variable by multivariate analysis. During the initial 3 postoperative years, yearly tumor recurrence rate was 22% in cirrhotic patients and 15% in noncirrhotic patients. In cirrhotic patients, the recurrence rate did not decrease even after three years of tumor-free survival post-resection, whereas in noncirrhotic patients the recurrence rate decreased to 9%. Cirrhosis was associated with a higher probability of recurrence exceeding the Milan criteria. CONCLUSIONS: Hepatic resection offers an acceptable survival result for HCC patients fulfilling the Milan criteria. Coexisting cirrhosis is associated with higher mortality and recurrence rate, possibly due to multicentric carcinogenesis which limits the efficacy of hepatic resection.     

Can we expand the indications for liver transplantation among hepatocellular carcinoma patients with increased tumor size?

INTRODUCTION: Due to the scarcity of donors and the fact that size is the main prognostic factor, Milan criteria have been used since 1996 to select hepatocellular carcinoma (HCC) patients for liver transplantation. In 2001 UCSF criteria showed that including layer tumors did not reduce the survival results. The objective of this paper was to evaluate whether HCC tumor sizes exceeding the Milan criteria adversely influence survival rates. PATIENTS AND METHODS: Between May 1988 and July 2001, 53 patients were transplanted due to HCC and cirrhosis. The etiology of cirrhosis was HCV in 23 cases and HBV in 6. In 11 cases the HCC were incidental by discovered namely, a mean/ diameter of 1.8 cm (versus 2.6 cm in nonincidental HCC). Sixty-two percent of tumors met the Milan criteria, and 68% the USCF criteria. RESULTS: The actuarial survival was 79% at 1 year and 62% at 5 years. The survival of patients with incidental HCC was 82% at 1 year and 82% at 5 years, which is better than the survival of those with nonincidental HCC (78% at 1 year and 57% at 5 years, P<.05). According to Milan criteria, the survival patients with early tumors was 82% at 1 year and 68% at 5 years, and for advanced tumors (NS), 75% and 54%, respectively. Comparison of early versus advanced tumors according to UCSF criteria showed survivals of 84% versus 64% at 1 year (P<.05) and 67% versus 48% at 5 years (P<.05), respectively. CONCLUSION: Increasing the HCC size among LT according to the California criteria did not reduce survival rates compared with the Milan criteria.     

Accuracy of staging as a predictor for recurrence after liver transplantation for hepatocellular carcinoma

BACKGROUND: Tumor number, size, and macrovascular invasion (MacroVI) are the most widely used predictors of survival after liver transplantation (LT) for hepatocellular carcinoma (HCC). We analyzed all patients undergoing LT for HCC at our center to establish the accuracy of preoperative clinical staging and to determine which patients have a higher probability of being understaged. METHODS: In all, 118 patients with confirmed HCC after LT from April 1991 to October 2004 at our institution were reviewed. All patients were monitored with serial imaging every 3 months to ensure their eligibility for LT within Milan criteria. Understaging in the 118 patients was defined as evidence on explant pathology that Milan criteria (TNM stage pT1 or pT2) had been exceeded. RESULTS: Five-year DFS was 78% with a recurrence rate of 15% after a median follow-up after LT of 30 months. On explant pathology, 43% (51/118) of patients exceeded Milan criteria and had a worse DFS (1 year, 95% vs. 87%; 3 year, 87% vs. 64%; P=0.03) compared to those who met LT criteria. Understaging was more likely in patients with imaging characteristics of > or = 2 tumor nodules (P=0.005) and tumor growth > 0.25 cm/month (P=0.02) and pathologic findings of vascular invasion (P=0.001) and bilobar tumors (P=0.002). CONCLUSIONS: Preoperative imaging every 3 months while on the waiting list frequently understages HCC as assessed by explant pathology. Recurrence after LT often occurred in patients that were understaged. Improving the accuracy of clinical staging and inclusion parameters will ensure proper organ allocation and acceptable outcomes after LT.     

Comparison of clinical and pathological staging and long-term results of liver transplantation for hepatocellular carcinoma in a single transplant center

Liver transplantation (OLT) is a treatment for hepatocellular carcinoma (HCC) superimposed on cirrhosis provided that the disease meets defined criteria. The aim of the study was to evaluate our experience with respect to clinical and pathological staging and long-term results. From 1996 to 2005, 50 patients underwent OLT for HCC including 43 men (86%) and seven women (14%) of median age 57 years (range 37 to 67). All patients fulfilled the Milan criteria. The HCC diagnosis was based on preoperative imaging and alpha-fetoprotein levels; no tumor biopsy was performed. Upon histological examination of the resected specimens, we discovered 6 (12%) incidentalomas and 8 (16%) cases of no HCC. Finally we had 42 "true" HCC. Twenty-six patients (52%) have been downstaged and 10 (20%) upstaged by preoperative imaging; 15% were pT1, 45% were pT2, 27% pT3, and 13% pT4a. Twenty-six percent of cases exceeded the Milan criteria. One patient (pT4a) with microvascular invasion died of pulmonary metastases at 14 months after transplantation. No HCC recurrences within the liver have been encountered at a median follow-up of 20 months (range 0 to 80 months). Overall the estimated 1-, 3-, and 5-year survival rates were 83%, 77%, and 72%, respectively. One-, 3-, and 5-year estimated survival rates were 87%, 75%, and 75% for pT1, and pT2, and 75%, 67%, and 67% for pT3 and pT4a, respectively (P = .99). Based on our experience OLT for HCC has long-term results comparable to those without HCC despite the presence of a significant number of cases exceeding the Milan criteria upon pathological staging.     

Liver transplantation for hepatocellular carcinoma: further considerations on selection criteria.

The selection criteria in liver transplantation for HCC are a matter of debate. We reviewed our series, comparing two periods: before and after 1996, when we started to apply the Milan criteria. The study population was composed of patients with a preoperative diagnosis of HCC, confirmed by the pathological report and with a survival of >1 year. Preoperative staging as revealed by radiological imagining was distinguished from postoperative data, including the variable of tumor volume. After 1996 tumor recurrences significantly decreased (6 out of 15 cases, 40% vs. 3 out of 48, 6.3%, P < .005) and 5-year patient survival improved (42% vs. 83%, P < .005). Not meeting the Milan criteria was significantly related to higher recurrence rate (37.5% vs. 12.7%, P < .05) and to lower 5-year patient survival (38% vs. 78%, P < .005%) in the preoperative analysis, but not in the postoperative one. The alfa-fetoprotein level of more than 30 ng/dL and the preoperative tumor volume of more than 28 cm3 predicted HCC recurrences in the univariate and mutivariate analysis (P < .005 and P < .05, respectively). The ROC curve showed a linear correlation between preoperative tumor volume and HCC recurrence. Milan criteria significantly reduced tumor recurrences after liver transplantation, improving long-term survival. In conclusion, the efficacy of tumor selection criteria must be analyzed with the use of preoperative data, to avoid bias of the postoperative evaluation. Tumor volume and alfa-fetoprotein level may improve the selection of patients.     

Extended indication for living donor liver transplantation in patients with hepatocellular carcinoma

BACKGROUND: Liver transplantation is an accepted treatment option for patients with otherwise untreatable hepatocellular carcinoma (HCC). The present study assessed the outcome of living donor liver transplantation (LDLT) under extended selection criteria based on a single-center experience. METHODS: A total of 60 patients who underwent LDLT for HCC were included. Our indication for LDLT included HCC without extrahepatic spread or macroscopic vascular invasion. The size and number of HCC nodules were not limited. Recurrence-free survival rates according to various factors were compared to identify risk factors for recurrence. RESULTS: Forty patients (67%) preoperatively exceeded the Milan criteria. The median follow-up was 437 days (range: 23-1,385 days). The overall 1- and 3-year actuarial survival rates were 88.4 and 68.6%, respectively. HCC recurred in eight patients (14.3%) within a mean follow-up of 288 days; all were patients who exceeded the Milan criteria. The 1-, 2- and 3-year recurrence-free survival rates of patients who fulfilled the Milan criteria were 100%, 100%, and 100%, respectively, whereas those of patients who exceeded the criteria were 83.0%, 74.0%, and 74.0%, respectively. Tumor diameter >5 cm was significantly associated with worse prognosis, but the number of tumors was not. A preoperative des-gamma-carboxy prothrombin value >300 mAU/ml was strongly associated with the high recurrence rate. These two variables were significant in multivariate analysis. CONCLUSIONS: LDLT was shown to offer acceptable results in patients who exceeded the Milan criteria. The indication for LDLT can therefore be expanded beyond the Milan criteria, especially for patients with small multiple tumors <5 cm.     

Effectiveness of locoregional therapy before living donor liver transplantation in patients with hepatocellular carcinoma who meet the Milan criteria

Background

Many patients are diagnosed with hepatocellular carcinoma (HCC) within the Milan criteria. In Korea, these patients are preferentially treated with locoregional therapy (LRT) instead of living donor liver transplantation. We investigated the effectiveness of LRT in liver transplant recipients who met the Milan criteria at the time of HCC diagnosis and investigated risk factors for HCC recurrence.

Methods

We retrospectively reviewed the medical records of patients diagnosed with HCC who met the Milan criteria between 2002 and 2008.

Results

We performed 101 liver transplants for HCC during the study period. Seventy-one patients (70%) underwent pretransplant LRT. The disease-free survival rates at 1, 3, and 5 years in patients who received LRT were 96.6%, 93.1%, and 93.1%, and in those who did not receive LRT, 94.2%, 83.4%, and 83.4%, respectively. There were no differences between the 2 groups. Multivariate analysis showed that a low Model for End-Stage Liver Disease (MELD) score and microvascular invasion were independent predictors of HCC recurrence after transplantation. The MELD scores and rate of microvascular invasion were not statistically different in patients with or without previous LRT.

Conclusion

Pretransplant LRT for patients with HCC who met the Milan criteria at the time of diagnosis did not provide a clear benefit with respect to HCC recurrence after transplantation. If patients have suitable living donors, those who meet the Milan criteria should undergo a liver transplantation as soon as possible.     

Living Donor Liver Transplantation Versus Deceased Donor Liver Transplantation for Hepatocellular Carcinoma Within or Beyond the Milan Criteria: Comparable Long-Term Outcomes

BackgroundThe long-term outcomes after living donor liver transplantation (LDLT) vs deceased donor liver transplantation (DDLT) for hepatocellular carcinoma (HCC) remain controversial. We compared the long-term outcomes between LDLT and DDLT in patients with HCCs within or beyond the Milan criteria.MethodsThis retrospective study included 896 patients who underwent liver transplantation (829 LDLTs and 67 DDLTs) for HCC from June 2005 to May 2015. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan–Meier method with log-rank test.ResultsRFS at 1, 3, 5, and 10 years after LDLT was 89.6%, 84.6%, 82.4%, and 79.6%, respectively, and, after DDLT, was 92.4%, 86.2%, 82.4%, and 82.4%, respectively, and OS at 1, 3, 5, and 10 years after LDLT was 96.1%, 88.1%, 85.6%, and 82.7%, respectively, and, after DDLT, was 97.0%, 83.6%, 82.1%, and 77.3%, respectively, with no significant differences in RFS (P = .838) or OS (P = .293) between groups. No statistically significant differences after LDLT or DDLT were identified in RFS (89.8% vs 98.1%, respectively, at 5 years; P = .053) or OS (90.4% vs 90.6% , respectively, at 5 years; P = .583) for HCCs meeting the Milan criteria as well as for those beyond the Milan criteria (RFS, 37.8% vs 28.6%, respectively, at 5 years; P = .560 and OS, 57.3% vs 50.0%, respectively, at 5 years; P = .743).ConclusionsPatients who underwent LDLT for HCCs showed comparable long-term outcomes to patients who underwent DDLT. Patients with HCCs within the Milan criteria demonstrated acceptable long-term outcomes after both LDLT and DDLT.