Patients Meeting Milan Criteria Research Articles

Radiofrequency ablation with or without transarterial chemoembolization for hepatocellular carcinoma meeting Milan criteria: a focus on tumor progression and recurrence patterns.

The aim of this study was to evaluate tumor progression and recurrence patterns of radiofrequency ablation (RFA) with or without transarterial chemoembolization (TACE) for treating hepatocellular carcinoma (HCC) that meets Milan criteria. This retrospective study included consecutive HCC patients meeting Milan criteria who underwent percutaneous RFA with or without TACE as initial treatment at a tertiary academic center between December 2017 and 2022. Technical success rate, local recurrence-free survival (LRFS), progression-free survival (PFS) and recurrence patterns were recorded. A total of 135 HCC patients (109 male [80.7%]) with a mean age of 62 years and 147 target lesions were retrospectively enrolled. The technical success rate was 99.3%. The median LRFS was 60 months, and the cumulative 1-, 3-, and 5-year LRFS were 88.9%, 70.1%, and 30.0%, respectively. Additionally, the median PFS was 23 months, with cumulative 1-, 3-, and 5-year PFS of 74%, 30%, and 0%, respectively. Multivariate analysis confirmed that age > 60, alpha-fetoprotein (AFP) (> 10), and albumin were associated with PFS (2.34, p = 0.004; 1.96, p = 0.021; 0.94, p = 0.007, respectively). Six recurrence patterns were identified: local tumor progression (LTP) alone (n = 15, 25.0%), intrahepatic distant recurrence (IDR) alone (n = 34, 56.7%), extrahepatic recurrence (ER) alone (n = 2, 3.3%), IDR + ER (n = 2, 3.3%), LTP + IDR (n = 5, 8.8%), and LTP + IDR + ER (n = 2, 3.3%). IDR occurred most frequently as a sign of good local treatment. RFA in combination with TACE does not appear to provide an advantage over RFA alone in improving tumor progression in patients with HCC meeting the Milan criteria. However, further prospective studies are needed to confirm these findings and to determine the optimal treatment approach for this patient population.

Liver Stereotactic Body Radiation Therapy (SBRT) to Downstage Patients with Hepatocellular Carcinoma prior to Liver Transplant

Orthotopic liver transplantation (OLT) marks the most successful treatment for hepatocellular carcinoma (HCC) patients meeting Milan criteria. The process of reducing the disease burden of HCC patients not currently meeting criteria for OLT with local therapy is referred to as "downstaging" and has proven to be a feasible approach. RTOG 1112 recently demonstrated the efficacy and acceptable toxicity of liver SBRT for treating HCC. However, limited data currently exists describing the efficacy of SBRT for downstaging HCC patients and facilitating OLT. A single institution IRB approved prospective liver SBRT registry was surveyed for all patients outside of Milan criteria (1 lesion >5 cm; 2-3 lesions >3 cm) without vascular invasion or extrahepatic disease. Patients felt least likely to become OLT candidates with downstaging (age >80, >4 lesions, lesion >12 cm) were excluded. The primary endpoints were downstaging and OLT. Secondary endpoints were time to transplant, local control (LC), recurrence free survival (RFS) and overall survival (OS). A total of 38 HCC patients with a median age of 65 years (range 28 - 80) met inclusion criteria. Median follow up was 14 months (IQR 3 - 35). At baseline, median KPS was 80 (range 60 - 100) with 16 Child-Pugh (CP) A (42%), 13 CP B (34%), and 9 CP C patients (24%). All patients were outside of Milan criteria and 25 patients (66%) were outside of UCSF criteria at time of SBRT. No patients had extrahepatic disease or vascular invasion. Median number of lesions, largest tumor size, and total sum of lesions were 2 (range 1 - 4), 5.0 cm (IQR, 4.0 - 6.5), and 6.6 cm (IQR 5.9 - 9.2), respectively. Prior to SBRT, 22 patients (58%) had received non-SBRT local therapy. At time of SBRT a variety of dose fractionation schedules were selected with a median BED10 of 78 (IQR 62 - 100). Concurrent sorafenib was used in 2 patients (8%). Following completion of SBRT, 21 patients (55%) were successfully downstaged at a median 3.0 months (IQR 1.9 - 6.1) after treatment, most frequently secondary to decrease in size of the largest lesion (86%). Twelve patients (32%) proceeded to undergo OLT at a median 7 months (IQR 3 - 14) after SBRT and 105 days (IQR 18 - 344) following successful downstaging. Of the 25 patients initially exceeding UCSF criteria, 7 (28%) underwent OLT. Among those receiving OLT, 5 patients (42%) remain alive without evidence of disease, 3 patients (25%) have recurred, 3 patients (33%) died within 2 years from transplant complications, and 1 patient (8%) died from an unrelated cause. LC at 2 years was 83%. Median RFS and OS for the overall cohort were 7 months (95% CI 0 - 21) and 24 months (95% CI 11 - 36), respectively. Among the transplant recipients, the median OS was 37 months (95% CI 30 - 44) compared to 15 months (95% CI 6 - 23) among those not receiving transplant. With careful patient selection, liver SBRT serves as a feasible downstaging method to facilitate OLT in HCC patients.

Descriptive Analysis of Everolimus Conversion in Liver Transplant Recipients With Malignant Neoplastic Disease

BackgroundCalcineurin inhibitors are associated with the development of de novo tumors and increased recurrence of hepatocellular carcinoma after liver transplant. It has been suggested that mammalian target of rapamycin inhibitors (everolimus [EVR]) may improve prognosis. We analyzed our experience on the use of EVR in malignant neoplasms in liver transplantation. Methods. We performed a retrospective descriptive analysis of 477 transplants performed between 2002 and 2019 at Virgen de las Nieves Hospital. A total of 100 patients received EVR; 23 transplants were because of tumor disease (23%), with de novo tumor in 12 patients and hepatocarcinoma in 11. The statistical study was carried out using the statistical program SPSS 17.0 software. ResultsThe study included 18 male patients (78.3%) and 5 female patients (21.7%) with an average age of 59.67 years. The most common indications of liver transplant have been alcoholic cirrhosis in 39% and hepatitis C virus cirrhosis in 21.7%. De novo tumors were lung neoplasm in 4 patients (33.3%), lymphoma in 2 patients(16.7%), oropharynx in 2 patients (16.7%), skin tumors in 2 patients (16.7%), and a kidney tumor (8.3%) in 1 patient. As for hepatocellular carcinoma, 8 patients met Milan criteria on the explant (61.5%). Tacrolimus was discontinued in all cases. The average onset time of post-transplant EVR was 2231.42 days in the de novo neoplasms and 307.45 days in those receiving transplants because of hepatocellular carcinoma (P = .05). We observed 5 deaths (21.7%). ConclusionAlthough the beneficial long-term role of EVR in liver transplant recipients with tumor disease is not demonstrated, it is used by most transplant units, both in de novo neoplasms and those receiving transplants because of hepatocellular carcinoma.

Living Donor Liver Transplantation for Hepatocellular Carcinoma: A Single-Center Experience from Pakistan

Living donor liver transplantation (LDLT) is an established treatment for patients with cirrhosis and hepatocellular carcinoma (HCC) within Milan criteria. Acceptable outcomes have been demonstrated in patients fulfilling extended criteria. Here, we share our experience with LDLT for patients with HCC within and beyond Milan criteria, with emphasis on poor prognostic factors. We retrospectively reviewed patients who underwent LDLT between 2012 and 2017 and had HCC proven on explant liver histopathology. A total of 117 patients were included. Patients who died early after transplant (in <30 days) were excluded. For outcomes, patients were divided into prognostic groups. These groups were based on (1) alpha fetoprotein >600, (2) poor differentiation, and (3) the presence of lymphovascular invasion. Recurrence-free survival (RFS) was determined using Kaplan-Meier curves. Median age was 53 (30-73) years. Median follow-up was 20.3 (1-63.2) months. Median model for end stage liver disease (MELD) score was 19 (9-34). Of a total of 117 patients, 74 (63.2%) patients met Milan criteria. Recurrence rate was 12/117 (10.3%). Actuarial 5-year RFS was 88% and 82% (P=0.3) in patients within and outside Milan criteria. There was no difference in 3-year RFS in patients with 0, 1, or 2 poor prognostic factors within Milan criteria (92%, 87%, and 75%, respectively; P=0.3). However, a significant difference in RFS was seen in patients outside Milan criteria (92%, 93%, and 53%; P=0.03). Patients within Milan criteria have acceptable RFS even in the presence of poor prognostic factors. However, the presence of two or more poor prognostic variables significantly impacts RFS of patients outside Milan criteria.

Liver Resection for Neuroendocrine Tumor Liver Metastases Within Milan Criteria for Liver Transplantation

BackgroundThe role of liver transplant (LT) for neuroendocrine liver metastasis (NELM) has not been completely defined. While international guidelines included LT as a potential treatment for highly selected patients with advanced NELM, recently, LT has been proposed as an alternative curative treatment for NELM for patients meeting restrictive criteria (Milan criteria). MethodsUsing a multi-institutional cohort of patients undergoing liver resection for NELM, the long-term outcomes of patients meeting Milan criteria (resected NET drained by the portal system, stable disease/response to therapies for at least 6 months, metastatic diffusion to < 50% of the total liver volume, a confirmed histology of low-grade, and ≤ 60 years) were investigated. ResultsAmong the 238 patients included in the study, 28 (12%) patients met the Milan criteria for LT with a 5-year OS of 83%. Furthermore, among patients meeting Milan criteria, subsets of patients with favorable clinic-pathological characteristics had 5-year OS rates greater than 90% including G1 patients (5-year OS, 92%), patients undergoing minor liver resection (5-year OS, 94%), patients with low number of NELM (1–2 NELM), and small tumor size (< 3 cm) (for both groups of patients, 5-year OS, 100%). ConclusionsIn our series, only 12% of patients met Milan criteria, and the 5-year OS after liver resection for this small selected group of patients was comparable with that reported in the literature for patients undergoing LT for NELM within Milan criteria. While LT might be the optimal treatment for patients with unresectable NELM, surgical resection should be the first option for patients with resectable NELM.

Outcome of hepatitis B and C virus-associated hepatocellular carcinoma occurring after renal transplantation.

Kidney transplant recipients (KTR) are subjected to immunosuppressive therapy that can enhance hepatitis B and C virus replication, leading to cirrhosis and hepatocellular carcinoma (HCC). The aim of this study was to assess the prevalence and outcome of HCC in KTR. Case-control study. Patients with chronic HBV and/or HCV infection who underwent kidney transplantation between 1976 and 2011 and subsequently developed HCC were compared to a control group of patients with chronic HBV and/or HCV infection, matched for gender and age at HCC diagnosis, who did not receive kidney transplantation. Among 2944 KTR, 330 had hepatitis B and/or C. Fourteen developed HCC, a period prevalence of 4.2%. Age at HCC diagnosis was 52.6±6.5years (53.5±5.7 in controls, P=.76). Time between transplantation and HCC diagnosis was 16.7±2.7years. Six HCCs were related to HBV, six to HCV and two to co-infection with HBV and HCV. Immunosuppressive therapy was comparable in HBV, HCV and HBV+HCV patients. At diagnosis, 71% of patients met Milan criteria (65% in the control group, P=.4). Alpha-fetoprotein levels, tumour characteristics and treatment modalities were comparable between both groups. Patient survival 2years after HCC diagnosis was 28% in KTR, compared to 68% in controls (P=.024). Survival after HCC diagnosis is significantly worse in KTR compared to nontransplanted patients with HBV and/or HCV. Prevention is crucial and should be based on viral eradication/suppression before or after transplantation.

Recurrence after liver transplantation for hepatocellular carcinoma according to up-to-seven criteria.

The Up7 criteria for HCC have recently emerged to identify potential candidates for OLT. The aim of this study was to assess the validity of the Up7 criteria according to the pathological analysis of the explanted livers. For recurrence risk calculation 669 HCC transplanted patients were classified according to both the pathological Milan and Up7 criteria. In order to identify potential predictors of recurrence, selected biological tumor markers and morphological features were then tested by Cox regression. The 5-year HCC recurrence rate for the Milan out/Up7 in subgroup (n=87), was significantly higher than patients meeting Milan criteria (n=299), 15.8% vs. 9.4% (p=0.0290). For patients within the Up7 criteria (n=383), only pre-OLT AFP level >1000ng/mL and microvascular invasion were significant predictors for recurrence, and for those beyond the Up7 criteria (n=286), pre-OLT AFP level >1000ng/mL, poor differentiation grade and microvascular invasion remained significant. Compared to the current Milan staging system, HCC patients within the pathological Up7 criteria were associated with a higher, but acceptable risk of recurrence after OLT, and along with tumor burden, other parameters can potentially be used for further refinement of HCC staging, such as AFP levels and microvascular invasion.

Su1286 Differences Between Community and Academic Cohorts of Patients With Chronic Hepatitis B (CHB) in the Development of Hepatocellular Carcinoma (HCC)

G A A b st ra ct s CI = 19%-27%) for patients receiving only supportive care, 39% (95% CI = 32%-46%) for those receiving liver-directed palliative therapy, 61% (95%CI = 51%-70%) for those undergoing partial hepatectomy, and 77% (95% CI = 71%-82%) for those having a liver transplantation. In multivariate analysis (Table), independent predictors for improved survival were non-White/non-Black race, palliative as well as surgical treatment. Independent predictors for poorer survival were age older than 65 and Black race (compared toWhites). Conclusions: In spite of improved opportunity for both effective palliative and curative therapies in the recent years, almost half of patients meeting Milan criteria are still not undergoing any therapy. In addition to assessing the efficacy and survival impact of current therapies, it is also important to focus on why so many patients diagnosed with HCC are not undergoing any treatment and reasons for continued existence of racial disparities. Early diagnosis through better screening protocols together with patient and physician education is crucial to achieve better outcomes. Multivariate Cox Proportional Hazards Model Assessing Factors Associated with Survival

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.

Orthotopic Liver Transplantation in Patients with Mixed Hepatocellular Carcinoma-Cholangiocarcinoma

Introduction: Primary liver cancer arises from hepatocytes or biliary epithelium resulting in hepatocellular carcinoma or cholangiocarcinoma, respectively. Mixed hepatocellular carcinoma-cholangiocarcinomas are rare; therefore, medical literature addressing these tumors is limited. As treatment modalities for mixed hepatocellular carcinoma-cholangiocarcinomas are few, the role of orthotopic liver transplantation remains controversial. Aim: To determine the survival outcomes of patients with incidentally discovered mixed hepatocellular carcinomacholangiocarcinomas after orthotopic liver transplantation. Methods and Materials: We present five patients with mixed hepatocellular carcinoma-cholangiocarcinomas who received orthotopic liver transplantation at our institution between September 1998 and July 2011. Characterization of the combined lesion was based on the Allen and Lisa classification scheme: type A: separate neoplasms of liver cell or bile duct cell; type B: different masses that mingle as they grow; and type C: masses that display both features of liver and bile duct cells. Results: Preoperatively, all patients met Milan criteria based on presumed hepatocellular carcinoma prior to orthotopic liver transplantation. Multifocal disease was present in all patients on pathological diagnosis, which was not appreciated during preoperative screening, and histologic characterization of the lesions revealed both Allen and Lisa types A (60%) and C (40%). All of our patients had underlying cirrhosis. The post-operative course was uneventful in all of the cases. Vascular invasion was observed in one patient who developed bone metastases and subsequently died 600 days post-transplant despite post-transplant chemoradiation therapy. The other four patients have remained disease-free; the mean overall survival is 800 days. Our population is unique in prevalence of cirrhosis and multiple hepatic lesions as compared to other case series. Conclusions: Although orthotopic liver transplantation is not recommended for patients with known mixed hepatocellular carcinoma-cholangiocarcinomas, in the event that a patient is transplanted, this case series shows that orthotopic liver transplantation is an acceptable treatment modality with appropriate survival outcomes.

Rates of Surveillance and Management of Hepatocellular Carcinoma in Patients Evaluated at a Liver Transplant Center

The treatment of choice for HCC with cirrhosis is liver transplantation (LT). We assessed if patients evaluated for hepatocellular carcinoma are being diagnosed by surveillance, the proportion of patients meeting Milan criteria at diagnosis, and rates of liver transplantation. All HCC cases in cirrhotic patients at Duke University Medical Center in the MELD era (Feb 2002-Oct 2008) were identified. Surveillance was defined as an imaging exam for detection of HCC in the 12 months prior to diagnosis of HCC. Logistic regression was used to examine predictors of LT. There were 319 cases meeting diagnostic criteria for HCC. Only 30.7% were diagnosed by surveillance and 43.7% met Milan criteria at diagnosis. Patients diagnosed by surveillance were more likely to meet Milan criteria and to receive LT (p < 0.0001 for both outcomes). Surveillance was associated with higher rates of LT with an OR 2.6 (95% CI 1.2-5.7, p = 0.02). Patients managed by a hepatologist were more likely to be diagnosed by surveillance (65.9 vs. 19.0%, p < 0.0001). Patients meeting Milan criteria managed by a hepatologist were more likely to receive LT than those referred from other providers (26.4 vs. 8%, p = 0.009). A minority of HCC cases in cirrhotic patients were diagnosed by surveillance, and only 12.5% underwent LT. Patients diagnosed by surveillance were more likely to meet Milan criteria and to undergo LT. These findings highlight the need for increased identification of patients with chronic liver disease and for subsequent referral to hepatologists for enrollment in HCC surveillance programs.

Outcome of Hepatic Resection for Hepatocellular Carcinoma within the Milan Criteria in Child-Pugh Class A Patients

Purpose: Hepatic resection and liver transplantation are considered a curative treatment for hepatocellular carcinoma (HCC) within the Milan criteria. In this study, we examine the outcome of hepatic resection for HCC within the Milan criteria, and determine the effectiveness of hepatic resection as the primary treatment for HCC within the Milan criteria in Child-Pugh class A. Methods: 110 patients underwent curative surgical resection for HCC in Child-Pugh class A between August 1991 and June 2008. Fifty-six patients met Milan criteria (Group M) and the remaining 54 did not (Group N). Results: Overall survival rates at 1, 3, and 5 years were 92.6%, 72.5% and 54.6% versus 70.4%, 43.1%, and 28.7 % in Group M and Group N, respectively (P=0.0043). The corresponding disease-free survival rates were 81.5%, 69.7%, and 38.2% versus 46.0%, 32.9%, and 26.9% in Group M and Group N (P=0.0012). HCC recurred in 25 patients in Group M (44.6%) and 35 patients in Group N (64.8%)(P=0.034). Outcomes of hepatic resection in Group M were significantly better compared to Group N. Conclusion: Hepatic resection can achieve a comparable 5-year overall survival & disease-free survival to that reported for liver transplantation. Hepatic resection should be considered as the standard therapy for HCC within the Milan criteria in Child-Pugh class A patients. (J Korean Surg Soc 2010;79:49-57)

Impact of Tumor Characteristic on the Outcome of Liver Transplantation in Patients With Hepatocellular Carcinoma

Introduction Orthotopic liver transplantation (OLT) is a well-established treatment for cirrhotic patients with hepatocellular carcinoma (HCC) who meet the Milan criteria. The aim of this study was to identify predictors of survival among 65 patients with HCC in cirrhotic livers who underwent liver transplantation (OLT). Methods From January 2001 to December 2008, we performed 655 OLT in 615 patients. HCC was diagnosed in 58 patients before OLT and in 65 by histological examination of the explanted livers; 74% of the patients met Milan criteria by histological examination. Results The median follow-up was 27 months (range = 1–96). We analyzed patient age and gender, etiology of liver disease, Child score at transplantation, rejection episodes, tumor number/size, vascular invasion, and differentiation grade. There was no significant difference in survival among patients grouped according to the Model for End-stage Liver Disease staging system for HCC. The 5-year survival of patients with low differentiated (G3) HCC was significantly worse than that of those with moderately differentiated (G2) or well-differentiated (G1) HCC: 50%, 81%, and 86% respectively, ( P < .01). Patients with microvascular invasion displayed a worse 5-year survival than those without vascular invasion (42% vs 80%; P < .01). Conclusions The analysis indicated that the histological grade of the tumors and evidences of microscopic vascular invasion were the most useful predictive factors for overall survival among patients with cirrhosis after liver transplantation for HCC.

Results of Hepatectomy as First Treatment for Hepatocellular Carcinoma within the Milan Criteria with Preserved Liver Function

Purpose: Hepatic resection and liver transplantation are surgical therapeutic options for small-sized HCC. But, the therapeutic option for patients meeting the Milan criteria with preserved liver function is facing a dilemma. In this study, we examined the outcomes of surgical resection for HCC patients meeting the Milan criteria with preserved liver function and rationale of hepatic resection as the first treatment for HCC meeting the Milan Criteria. Methods: Between 1991 and 2006, 248 patients with HCC underwent hepatectomy in 158 primary HCC patients meeting Milan criteria (Group M) and in 90 patients beyond Milan criteria (Group N). Median age was 54.5 years in group M and 52.4 years in group N. Results: The tumor size, mean survival months, E-S grade and vascular invasion rate were significantly different between the two groups. 67 patients in group M and 22 patients in group N had intrahepatic recurrence after primary hepatectomy. The cumulative 1, 3, and 5-year survival rates were 91.9%, 74.5%, and 60.5% in intrahepatic recurrence group M after primary hepatectomy and 100%, 96.0%, and 90.5% in repeated hepatic resection for recurrent treatment in group M, respectively. Conclusion: Because of the high survival rate and long-term survival after adequate treatment of recurrence, primary hepatectomy is considered a reasonable option as first-line treatment for HCC meeting Milan criteria with preserved liver function.

Liver Transplantation Criteria For Hepatocellular Carcinoma Should Be Expanded

To assess the efficacy of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) and the impact of current staging criteria on long term survival. 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. : 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. 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. 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.

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.

Outcomes and Recurrence of Initially Resectable Hepatocellular Carcinoma Meeting Milan Criteria: Rationale for Partial Hepatectomy as First Strategy

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. 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. 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. 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.