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.)     

肝癌肝移植的标准及其与预后的关系

目的 评价肝移植治疗肝细胞癌的价值以及受者选择对病人术后存活的影响.方法 对我院2000年6月至2007年2月实施的63例原发性肝细胞癌肝移植临床资料进行回顾性分析.采用kaplan-meier法进行生存率统计分析.结果 63例原发性肝细胞癌病人肝移植术后1、3、5年累积生存率分别为77.4%、59.3%、48.9%.符合Milan标准、符合UCSF标准和不符合UCSF标准受者,肝移植术后1、3、5年累积生存率分别为93.8%、92.1%、29.2%;80.8%、79.2%、8.3%;80.8%、79.2%、0.符合Milan标准、符合UCSF标准和不符合UCSF标准受者,术后1、2、3年肿瘤累积复发率分别为6.2%、15.5%、19.2%;7.9%、15.9%、20.8%;70.8%、87.5%、91.7%(P＜0.01).但是,符合UCSF标准与符合Milan标准受者移植术后累积生存率和肝癌累积复发率相似(P＞0.05).结论 以UCSF标准筛选肝癌病人进行肝移植不仅扩大了肝癌肝移植的适应证,还可以取得与Milan标准同样的效果.     

Liver Transplantation for Hepatocellular Carcinoma: Validation of the UCSF-Expanded Criteria Based on Preoperative Imaging

We previously suggested that in patients with heptocellular carcinoma (HCC), the conventional Milan criteria (T1/T2) for orthotopic liver transplantation (OLT) could be modestly expanded based on pathology (UCSF criteria). The present study was undertaken to prospectively validate the UCSF criteria based on pretransplant imaging. Over a 5-year period, the UCSF criteria were used as selection guidelines for OLT in 168 patients, including 38 patients exceeding Milan but meeting UCSF criteria (T3A). The 1- and 5-year recurrence-free probabilities were 95.9% and 90.9%, and the respective survivals without recurrence were 92.1% and 80.7%. Patients with preoperative T1/T2 HCC had 1- and 5-year recurrence-free probabilities of 95.7% and 90.1%, respectively, versus 96.9% and 93.6%, respectively, for preoperative T3A stage (p = 0.58). Under-staging was observed in 20% of T2 and 29% of T3A HCC (p = 0.26). When explant tumor exceeded UCSF criteria (15%), the 1- and 5-year recurrence-free probabilities were 80.4% and 59.5%, versus 98.6% and 96.7%, respectively, for those within UCSF criteria (p < 0.0001). In conclusion, our results validated the ability of the UCSF criteria to discriminate prognosis after OLT and to serve as selection criteria for OLT, with a similar risk of tumor recurrence and under-staging when compared to the Milan criteria.     

A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation.

In patients with hepatocellular carcinoma (HCC) exceeding conventional (T2) criteria for orthotopic liver transplantation (OLT), the feasibility and outcome following loco-regional therapy intended for tumor downstaging to meet T2 criteria for OLT are unknown. In this first prospective study on downstaging of HCC prior to OLT, the eligibility criteria for enrollment into a downstaging protocol included 1 lesion >5 cm and < or =8 cm, 2 or 3 lesions at least 1 >3 cm but < or =5 cm with total tumor diameter of < or =8 cm, or 4 or 5 nodules all < or =3 cm with total tumor diameter < or =8 cm. Patients were eligible for living-donor liver transplantation (LDLT) if tumors were downstaged to within proposed University of California, San Francisco (UCSF) criteria.13 A minimum follow-up period of 3 months after downstaging was required before cadaveric OLT or LDLT, with imaging studies meeting criteria for successful downstaging. Among the 30 patients enrolled, 21 (70%) met criteria for successful downstaging, including 16 (53%) who had subsequently received OLT (2 with LDLT), and 9 patients (30%) were classified as treatment failures. In the explant of 16 patients who underwent OLT, 7 had complete tumor necrosis, 7 met T2 criteria, but 2 exceeded T2 criteria. No HCC recurrence was observed after a median follow-up of 16 months after OLT. The Kaplan-Meier intention-to-treat survival was 89.3 and 81.8% at 1 and 2 yr, respectively. In conclusion, successful tumor downstaging can be achieved in the majority of carefully selected patients, but longer follow-up is needed to further access the risk of HCC recurrence after OLT.     

Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with a short waiting time.

Orthotopic liver transplantation (OLT) indication for hepatocellular carcinoma (HCC) is currently based on the Milan criteria. The University of California, San Francisco (UCSF) recently proposed an expansion of the selection criteria according to tumors characteristics on the explanted liver. This study: 1) assessed the validity of these criteria in an independent large series and 2) tested for the usefulness of these criteria when applied to pre-OLT tumor evaluation. Between 1985 and 1998, 479 patients were listed for liver transplantation (LT) for HCC and 467 were transplanted. According to pre-OLT (imaging at date of listing) or post-OLT (explanted liver) tumor characteristics, patients were retrospectively classified according to both the Milan and UCSF criteria. The 5-yr survival statistics were assessed by the Kaplan-Meier method and compared by the log-rank test. Pre-OLT UCSF criteria were analyzed according to an intention-to-treat principle. Based on the pre-OLT evaluation, 279 patients were Milan+, 44 patients were UCSF+ but Milan- (subgroup of patients that might benefit from the expansion), and 145 patients were UCSF- and Milan-. With a short median waiting time of 4 months, 5-yr survival was 60.1 +/- 3.0%, 45.6 +/- 7.8%, and 34.7 +/- 4.0%, respectively (P < 0.001). The 5-yr survival was arithmetically lower in UCSF+ Milan- patients compared to Milan+ but this difference was not significant (P = 0.10). Based on pathological features of the explanted liver, 5-yr survival was 70.4 +/- 3.4%, 63.6 +/- 7.8%, and 34.1 +/- 3.1%, in Milan+ patients (n = 184), UCSF+ Milan- patients (n = 39), and UCSF- Milan- patients (n = 238), respectively (P < 0.001). However, the 5-yr survival did not differ between Milan+ and UCSF+ Milan- patients (P = 0.33). In conclusion, these results show that when applied to pre-OLT evaluation, the UCSF criteria are associated with a 5-yr survival below 50%. Their applicability is therefore limited, despite similar survival rates compared to the Milan criteria, when the explanted liver is taken into account.     

Alpha-Fetoprotein as a Modifier of Anatomic Criteria for Transplantation of HCC Patients

BackgroundThe current listing criteria (Milan, University of California San Francisco [UCSF]) for orthotropic liver transplants (OLT) in hepatocellular carcinoma (HCC) patients emphasize the anatomic features of the tumor such as size, burden, and multiplicity. Recent reports showed that patients with large tumors may have equivalent survival to Milan criteria patients. This suggests that differences in biologic behavior of tumors may contribute to the outcome.AimThe aim of this article is to understand the impact of biologic modifiers such as alpha-fetoprotein (AFP) on survival in both Milan and UCSF HCC patients.MethodsWe reviewed all liver transplants reported to the United Network for Organ Sharing between 2002 and 2013. We analyzed the survival of patients transplanted for HCC who fit the Milan criteria and those transplanted with tumors beyond Milan and within UCSF criteria. We tested various AFP level cutoffs in both groups in relationship to the 1-, 3-, and 5-year survival rates below and above the proposed cutoffs.ResultsSurvival difference was significant between Milan patients with AFP ≤ 2500 ng/mL and those with AFP > 2500 ng/mL (59.1% vs 37.4%; P < .001). The mean 5-year survival was 55% for beyond Milan within UCSF patients with AFP ≤ 150 ng/mL and 35.7% for those with AFP > 150 ng/mL (P = .003).ConclusionAFP level should be incorporated in the selection criteria for HCC patients considered for OLT. Milan patients with an AFP level exceeding 2500 ng/mL have reduced survival. Patients with tumors beyond Milan and within UCSF criteria whose AFP ≤ 150 ng/mL achieve acceptable 5-year survival and are good candidates for OLT.     

肝移植治疗原发性肝癌103例疗效观察

目的 比较不同受体选择标准肝癌肝移植的远期疗效,分析肝痛肝移植术后肿瘤复发相关因素.方法 总结北京佑安医院2004年4月至2008年3月间的103例肝癌肝移植的临床资料,按照肿瘤的特征将其分为3组:符合米兰标准组(A组)、超出米兰标准但满足UCSF标准组(B组)和超出UCSF标准组(C组),比较3组的总体生存率及无瘤生存率,并分析影响远期预后的相关因素.结果 103例肝癌肝移植总体1、2、3年存活率分别为84.0%、70.5%和60.2%.其中A组50例,1、2、3年生存率和无瘤生存率分别为93.4%、83.8%、73.2%和97.3%、93.9%、88.7%;B组17例,1、2、3年生存率和无瘤生存率分别为93.3%、79.4%、66.2%和86.7%、79.4%、66.2%;C组36例,1、2、3年生存率和无瘤牛存率分别为67.0%、45.5%、34.1%和65.8%、50.0%、41.7%.远期生存率A组与B组比较无差异(P=0.631),A组、B组与C组比较具有统计学差异(P值分别为0.001,0.045).结论 米兰标准是肝癌肝移植最佳适应证,超出米兰标准但满足UCSF标准也可获得满意的远期疗效;肿瘤的分期和微血管侵犯是影响远期预后的风险因素.     

Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence.

Milan and University of California at San Francisco (UCSF) criteria are used to select patients with hepatocellular carcinoma (HCC) for liver transplantation (LT). Recurrent HCC is a significant cause of death. There is no widely accepted pathological assessment strategy to predict recurrent HCC after transplantation. This study compares the pathology of patients meeting Milan and UCSF criteria and develops a pathological score and nomogram to assess the risk of recurrent HCC after transplantation. All explanted livers with HCC from our center over the 18-yr period 1985 to 2003 were assessed for multiple pathological features and relevant clinical data were recorded; multivariate analysis was performed to determine features associated with recurrent HCC. Using pathological variables that independently predicted recurrent HCC, a pathological score and nomogram were developed to determine the probability of recurrent HCC. Of 75 cases analyzed, 50 (67%) met Milan criteria, 9 (12%) met only UCSF criteria and 16 (21%) met neither criteria based on explant pathology. There were 20 cases of recurrent HCC and the mean follow-up was 8 yr. Recurrent HCC was more common (67 vs. 12%; P < 0.001) and survival was lower (15 vs. 83% at 5 yr; 15 vs. 55% at 8 yr; P < 0.001) with those who met only UCSF criteria, compared to those who met Milan criteria. Cryptogenic cirrhosis (25 vs. 5%; P = 0.015), preoperative AFP >1,000 ng/mL (20 vs. 0%; P < 0.001) and postoperative OKT3 use (40 vs. 15%; P = 0.017) were more common among patients with recurrent HCC. While microvascular invasion was the strongest pathological predictor of recurrent HCC, tumor size >or=3 cm (P = 0.004; odds ratio [OR] = 7.42), nuclear grade (P = 0.044; OR = 3.25), microsatellitosis (P = 0.020; OR = 4.82), and giant/bizarre cells (P = 0.028; OR = 4.78) also predicted recurrent HCC independently from vascular invasion. The score and nomogram stratified the risk of recurrent HCC into 3 tiers: low (<5%), intermediate (40-65%), and high (>95%). In conclusion, compared to patients meeting Milan criteria, patients who meet only UCSF criteria have a worse survival and an increased rate of recurrent HCC with long-term follow-up, as well as more frequent occurrence of adverse histopathological features, such as microvascular invasion. Application of a pathological score and nomogram could help identify patients at increased risk for tumor recurrence, who may benefit from increased surveillance or adjuvant therapy.     

Liver transplantation outcomes for early-stage hepatocellular carcinoma: results of a multicenter study.

The incidence of hepatocellular carcinoma (HCC), a frequent and incurable complication of cirrhosis, continues to rise. Orthotopic liver transplantation (OLT) has been proposed as a treatment for unresectable, intrahepatic HCC limited in extent to the Milan criteria adopted by the United Network of Organ Sharing (UNOS) in 1998. More recently, somewhat less restrictive University of California, San Francisco (UCSF)10, criteria were proposed. To examine the long-term outcomes of OLT for HCC patients and to assess the UNOS policy of assigning weighted allocation points to patients with HCC, we retrospectively analyzed 144 patients (113 after 1998) with HCC who underwent OLT over an 11-year period at 3 institutions from UNOS Region 1. We compared their outcomes with 525 patients (272 after 1998) who underwent OLT for nonmalignant liver disease. The 1- and 5-year survival rates were 80.3% and 46.7%, respectively, for patients with HCC and 81.5% and 70.6%, respectively, for patients without HCC (P = .020). However, there was no difference in survival between HCC and non-HCC patients after implementation of disease-specific allocation for HCC in 1998. A higher proportion of the HCC cohort was older and male and had chronic HCV infection and alcoholic liver disease. In univariate analysis, having alpha-fetoprotein (AFP) levels of 10 ng/mL or less and meeting clinical and pathologic UCSF criteria were each significant predictors of improved survival (P = .005, P = .02, and P = .03, respectively). AFP greater than 10 ng/mL and exceeding pathologic UCSF criteria were also significant predictors of recurrence (P = .003 and P = .02, respectively). In conclusion, taken together, our data suggest that OLT is an acceptable option for patients with early HCC and that UCSF criteria predict outcome better than Milan or UNOS criteria. Regardless of which criteria are adopted to define eligibility, strict adherence to the criteria is important to achieve acceptable outcomes.     

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.     

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.     

Microvascular tumor embolism: independent prognostic factor after liver transplantation in hepatocellular carcinoma

Microscopic tumor cell dissemination may be a more important factor in the recurrence of hepatocellular carcinoma (HCC) after liver transplantation, probably because of posttransplant immunosuppression. The presence of microvascular tumor embolism was undetermined as a factor for HCC recurrence after orthotopic liver transplantation (OLT). This study evaluated whether microvascular tumor embolism affects recurrence-free survival and correlates with other clinicopathologic factors after OLT among patients with HCC. From September 1996 to June 2003, 72 OLTs for HCC were enrolled in this study. Median follow-up was 22.8 months. Among 41 patients without microvascular tumor embolism, 1-year, 2-year, and 5-year recurrence-free survival rates were all 97.6%, while these rates were 77.3%, 68.2%, and 59.7%, respectively, for 31 patients (43.1%) with microvascular tumor embolism (P = .0006). The 5-year recurrence-free survival rate showed significant differences for a pT2 tumor (P = .0073), for maximal tumor size <3 cm (P = .0328), for > or =5 cm solitary tumor (P = .0095), and for the presence of a tumor capsule (P = .0012), within the Milan criteria (P = .0376). At multivariate analysis, significant independent predictors for HCC recurrence were microvascular tumor embolism and histopathologic grade. In conclusion, microvascular tumor embolism is an independent predictor of HCC recurrence after liver transplantation. Although OLT is a safe and effective treatment for HCC within the Milan criteria, the presence of microvascular tumor embolism at pathologic examination can predict its recurrence. In these cases, the feasibility of immunosuppressive therapy or adjuvant chemotherapy must be considered to prevent tumor recurrence.     

Liver Transplantation for Hepatitis B Virus-Related Hepatocellular Carcinoma: One Center's Experience in China

Background

Hepatocellular carcinoma (HCC) is the fifth most common and the third most deadly cancer worldwide, with more than half a million identified cases and about a similar number of subjects succumb to it each year. This study sought to evaluate our results of liver transplantation for HCC to identify prognostic factors.

Methods

Between December 2001 and December 2006, 224 patients (205 men, 19 women; age range, 15-75 years) with HCC underwent orthotopic liver transplantation (OLT) at our center. All grafts were from deceased donors. There were 68 cases within Milan criteria (30.3%), 32 cases beyond Milan criteria but within UCSF (University of California, San Francisco) criteria (14.3%), and 124 cases beyond UCSF criteria (55.4%).

Results

The overall 1-, 3-, and 5-year patient cumulative survival rates were 82.5%, 60.1%, and 51.5%, respectively. The survival rates were comparable between patients within Milan and UCSF criteria, but were significantly greater than that of patients beyond UCSF criteria. Multivariate analysis revealed alpha fetoprotein (AFP) ≥ 800 μg/L, vascular invasion, and poor tumor differentiation to be independent prognostic factors.

Conclusion

OLT is a safe and effective treatment for hepatitis B virus-related HCC. Compared with Milan criteria, UCSF criteria successfully expanded the indication without deteriorating the prognosis significantly, while preoperative AFP ≥ 800 μg/L, vascular invasion, and poor tumor differentiation indicated poor survival.     

Predictive factors of outcome after liver transplantation in patients with cirrhosis and hepatocellular carcinoma

Studies to define the optimal upper limits of tumor size and number as predictors of outcome after orthotopic liver transplantation (OLT) have yielded conflicting results. We analyzed 72 patients with cirrhosis and hepatocellular carcinoma (HCC) who underwent OLT over a 12-year period in a single center. Predictive factors for survival and tumor recurrence, according to the Milan criteria, were also examined. Our cohort included 60 men and 12 women of mean age 54 +/- 8 years and mean follow-up of 40 +/- 39 months. Origin of cirrhosis was postviral in 70% and Child class B or C in two thirds of patients. HCC was multifocal in 61%; about one fifth of patients had micro- or macrovascular involvement or positive nodes upon histologic examination. The cumulative size of the lesions was <3 cm in 17 patients; >3 to < or =5 cm in 28 patients; >5 to < or =8 cm in 14 patients; and >8 cm in 13 patients. According to the number and size of tumor nodules, 49 patients met the Milan criteria. During follow-up 25 patients died, 13 due to tumor recurrence. The 1- and 2-year survivals were 90% and 85% for patients who met the Milan criteria versus 57% and 51% for patients exceeding those limits (P = .006). A cumulative tumor size >8 cm was predictive of survival and tumor recurrence upon multivariate analysis. The adoption of Milan criteria for selection of cirrhotic patients has improved survival and reduced the rate of tumor recurrence. The evaluation of cumulative tumor size might further improve patient selection.     

Impact of histological grade of hepatocellular carcinoma on the outcome of liver transplantation

HYPOTHESIS: Histological grade of hepatocellular carcinoma (HCC) is an important prognostic factor affecting patient survival after orthotopic liver transplantation (OLT). DESIGN: Retrospective analysis. SETTING: University-based teaching hospital. PATIENTS: Of 952 OLTs performed between June 1991 and January 1999, 56 OLT recipients had histologically proven HCC in the explant liver. Of those, 53 patients with complete clinicopathologic data were analyzed. A single pathologist blinded to the outcome of each patient reviewed all histological specimens. RESULTS: Median follow-up was 709 days. Overall survival for patients with tumors sized 5 cm or less at 1, 3, and 5 years was 87%, 78%, and 71%, respectively (Kaplan-Meier). Univariate analysis revealed the size, number, and distribution of tumors; the presence of microscopic vascular invasion and lymph node metastasis; histological differentiation; and pTNM stage to be statistically significant factors affecting survival. Multivariate analysis revealed histological differentiation and pTNM stage to be the independent and statistically significant factors affecting survival (P =.002 and.03, respectively). When pTNM stage was excluded from multivariate analysis, histological differentiation and size remained the significant independent factors (P =.02 and.03, respectively). Three-year survival for patients with small (5 cm) tumor with well- to moderately differentiated and poorly differentiated HCC was 62.5% and 0%, respectively. CONCLUSIONS: In our retrospective experience, histological differentiation had a statistically significant effect on the prognosis of HCC after OLT. However, before altering the current OLT selection criteria for patients with HCC, prospective studies are required to confirm the impact of histological grade on clinical outcome.     

The Impact of Pre-Operative Loco-Regional Therapy on Outcome After Liver Transplantation for Hepatocellular Carcinoma

No prior studies have shown that pre-operative loco-regional therapy for hepatocellular carcinoma (HCC) improves survival following orthotopic liver transplantation (OLT). We performed subgroup analyses according to pathologic HCC stage among 168 patients who underwent OLT to test the hypothesis that pre-operative loco-regional therapy confers a survival advantage in a subgroup at intermediate risk for HCC recurrence. Patients with pathologic T3 HCC meeting the proposed UCSF expanded criteria (single lesion not exceeding 6.5 cm or two to three lesions none > 4.5 cm with total tumor diameter within 8 cm) had a similar 5-year recurrence-free survival as patients with pathologic T2 HCC (88.5% vs. 93.8%; p = 0.56). In the subgroup with pathologic T2 or T3 HCC, the 5-year recurrence-free survival was 93.8% for the 85 patients who received pre-operative loco-regional therapy, versus 80.6% for the other 41 patients without treatment (p = 0.049). The treatment benefit, according to 5-year recurrence-free survival, appeared greater for pathologic T3 (85.9% vs. 51.4%; p = 0.05) than T2 HCC (96.4% versus 87.1%; p = 0.12). In conclusion, although the lack of a randomized controlled design precludes drawing firm conclusions, our results suggest that pre-operative loco-regional therapy may confer a survival benefit after OLT in the subgroup with pathologic T2 and T3 HCC.     

A revised scoring system utilizing serum alphafetoprotein levels to expand candidates for living donor transplantation in hepatocellular carcinoma

BACKGROUND: The development of living donor liver transplantation has stimulated discussion about the expansion of tumor burden limits for patients with hepatocellular carcinoma (HCC). Although serum alphafetoprotein (AFP) level is an important predictor of tumor recurrence, it is not included in the existing selection criteria for HCC in transplantation. METHODS: We performed a retrospective study of 63 consecutive adults with HCC diagnosed preoperatively who received living donor liver transplantation from February 1999 to September 2005 and survived over 1 month. The authors devised new scoring criteria that included tumor size, tumor number, and pretransplant AFP level as prognostic factors. The score of each parameter was classified from 1 to 4 points (tumor size, < or =3, 3.1 to 5, 5.1 to 6.5, >6.5 cm; tumor number, 1, 2 or 3, 4 or 5, or > or =6 nodules; and AFP, < or =20, 20.1 to 200, 200.1 to 1000, >1000 ng/mL, respectively). We defined that 3 to 6 points and 7 to 12 points were "transplantable" and "nontransplantable," respectively. The usefulness of the devised criteria was then investigated as a method of selecting candidates with HCC for transplantation. RESULTS: The candidates' overall 3-year survival rate and recurrence-free survival rate were 67% and 70% after transplantation, respectively. Based on pretransplant imaging, 37 (59%), 41 (65%), and 44 (70%) of the 63 patients met the Milan criteria, University of Californica, San Francisco (UCSF) criteria, and the new scoring criteria. Their 3-year survival rates were 80%, 78%, and 79%, respectively. Moreover, based on posttransplant data, the scoring criteria correlated with the risk of death and HCC recurrence (Milan criteria, P = .005 and .001; UCSF criteria, P = .013 and .001 for death and recurrence; scoring criteria, P < .001 for both). CONCLUSIONS: The newly devised scoring criteria could expand usefully current selection criteria for transplantation without detrimentally affecting outcome in the living donor transplantation setting for HCC.     

Antiviral prophylaxis and recurrence of hepatocellular carcinoma following liver transplantation in patients with hepatitis B

BACKGROUND: Orthotopic liver transplantation (OLT) is a viable treatment option for patients with hepatitis B (HBV) and concomitant hepatocellular carcinoma (HCC). However, cancer recurrence following transplantation approaches 20%. This study sought to identify the clinical and pathological factors associated with post-OLT survival. METHODS: Univariate and multivariate analyses considered the following variables: combination viral prophylaxis, HBV recurrence, tumor stage, vascular invasion, distribution, nodularity, pre- and post-OLT tumor size, pre-OLT alpha-fetoprotein (AFP), Milan and UCSF criteria, and Asian race. RESULTS: Cumulatively, HCC recurrence-free survival was 77%, 62%, and 53% at 1, 3, and 5 years, respectively, and was significantly better in patients who were free of viral recurrence post-OLT. Similarly, patients treated with combination prophylaxis had a significantly lower mortality than those who were not. CONCLUSIONS: Multivariate analysis revealed that AFP>500 ng/mL, presence of vascular invasion by explant, HBV recurrence, and combination prophylaxis were independent predictors of HCC recurrence-free survival.     

Number and Tumor Size Are Not Sufficient Criteria to Select Patients for Liver Transplantation for Hepatocellular Carcinoma

Background

Hepatocellular carcinoma (HCC) is an indication for liver resection or transplantation (LT). In most centers, patients whose HCC meets the Milan criteria are considered for LT. The first objective of this study was to analyze whether there is a correlation between the pathologic characteristics of the tumor, survival and recurrence rate. Second, we focused our attention on vascular invasion (VI).

Methods

From January 1997 to December 2007, a total of 196 patients who had a preoperative diagnosis of HCC were included. The selection criteria for LT satisfied both the Milan and the San Francisco criteria (UCSF). Demographic, clinical, and pathologic information were recorded.

Results

HCC was confirmed in 168 patients (85.7%). The median follow-up was 74?months. The pathologic findings showed that 106 patients (54.1%) satisfied the Milan criteria, 134 (68.4%) the UCSF criteria of whom 28 (14.3%) were beyond the Milan criteria but within the UCSF criteria, and 34 (17.3%) beyond the UCSF criteria. VI was detected in 41 patients (24%). The 1-, 3-, and 5-year overall survival rates were 90%, 85%, and 77%, respectively, according to the Milan criteria and 90%, 83%, and 76%, respectively, according to the UCSF criteria (P?=?NS). In univariate and multivariate analyses, tumor size and VI were significant prognostic factors affecting survival (P?400?ng/ml and tumor grade G3.

Conclusions

Tumor size and VI were the only significant prognostic factors affecting survival of HCC patients. Primary liver resection could be a potential selection treatment before LT.     

Multifocal manifestation does not affect vascular invasion of hepatocellular carcinoma: implications for patient selection in liver transplantation

BACKGROUND AND AIMS: Liver transplantation (OLT) for hepatocellular carcinoma (HCC) improves patient survival when tumor size and number are limited according to the Milan criteria. However, the impact of tumor size vs. the number of lesions for tumor recurrence after OLT is unclear. Microvascular invasion appears to be a significant risk factor for tumor recurrence. Therefore, it was the aim of this study to investigate tumor differentiation and microvascular invasion in relation to tumor number and size and their impact on survival after transplantation. PATIENTS AND METHODS: In 97 adult HCC patients who underwent OLT between June 1985 and December 2005 the incidence of microvascular invasion, tumor differentiation, and the number and size of tumor lesions were analyzed retrospectively. Their impact on survival was studied by multivariate analysis. RESULTS: Microvascular invasion was the only independent negative predictor of survival after OLT for HCC (p = 0.025). Tumor size > 5 cm was predictive for microvascular invasion (p = 0.007). In contrast, tumor number did not affect the incidence of microvascular invasion or cumulative survival. CONCLUSION: The size of the largest HCC lesion, but not the number of tumors, determined microvascular invasion, a predictor of the outcome following OLT for HCC. Thus, the number of HCC lesions should not be applied to patient selection prior to OLT. These data support the extension of the Milan criteria for the selection of HCC patients for OLT with regard to tumor number, but not tumor size.