Radiologic-histological correlation of hepatocellular carcinoma treated via pre-liver transplant locoregional therapies

Cleveland, USA

Radiologic-histological correlation of hepatocellular carcinoma treated via pre-liver transplant locoregional therapies

Galal El-Gazzaz, Achuthan Sourianarayanane, KV Narayanan Menon, Juan Sanabria, Koji Hashimoto, Cristiano Quintini, Dympna Kelly, Bijan Eghtesad, Charles Miller, John Fung and Federico Aucejo

Cleveland, USA

BACKGROUND:Locoregional therapies (LRTs) are treatments to achieve local control of hepatocellular carcinoma (HCC). Correlation between radiologic response to LRT and degree of induced tumor necrosis is not well understood. The aim of this study was to evaluate different levels of radiologic response after pre-liver transplant (LT) LRT and its correlation with percentage of tumor necrosis on explanted histopathology.

METHODS:Institutional Review Board approved LT database was queried for treated HCC in patients undergoing LT. Radiologic response was evaluated to predict tumor necrosis in the explanted liver. Tumor response was evaluated 1 to 3 months after LRT with computed tomography or MRI via Response Evaluation Criteria in Solid Tumors (RECIST), and European Association for the Study of the Liver (EASL) guidelines. LRT was repeated as needed until time of LT. Histological tumor necrosis was graded as complete (100%), partial (50%-99%), or poor (<50%).

RESULTS:Between 2002 and 2011, 128 patients (97 men and 31 women) received pre-LT LRT including transarterial therapy (93), radiofrequency ablation (20), or combination of both (15). The mean age of the patients was 58±9 years. Their mean follow-up was 35±27 months. The median waitlist time was 55 days. One hundred (78%) patients had HCC within the Milan criteria at the initial radiologic diagnosis. Nineteen (15%) of the patients had complete tumor necrosis on histopathology analysis. Fifty (39%) of the patients exhibited partial necrosis,52 (41%) showed poor or no necrosis and 7 (5%) showed progressive disease. The overall pre-LT radiologic staging was correlated with explant pathology in 73 (57%) of the patients. Underestimated tumor stage was noted in 49 (38%) patients, and overestimated tumor stage in 6 (5%) patients. The post-LT 3-year overall survival and disease free survival were 82% and 80%, and the rates for complete and partial tumor necrosis were 100% vs 78% (P=0.02) and 100% vs 75% (P=0.03), respectively.

CONCLUSIONS:In the current era, interpretation of radiologic response after LRT for HCC does not correlate accurately with histologic tumor necrosis. Total tumor necrosis is the goal of LRT; therefore, evolution in its performance is needed. Similarly, ways to predict therapy induced tumor necrosis via radiological investigation need to be improved.

(Hepatobiliary Pancreat Dis Int 2013;12:34-41)

locoregional therapy; radiologic response; hepatocellular carcinoma

Introduction

During the last decades the incidence of hepatocellular carcinoma (HCC) in the United States has tripled.[1,2]Worldwide, HCC is the sixth most common malignancy and is the third most common cause of cancer-related mortality.[1-4]Although surgical treatments (transplantation/resection) provide the best outcomes, most of patients present with advanced tumor stage and are not candidates for these options.

Locoregional therapies (LRT) including radiofrequency ablation (RFA), transarterial chemoembolization (TACE) and others, have been used as therapeutic alternatives for patients with HCC in both transplant and non-transplant scenarios.[5-7]

The role of pre-liver transplant (LT) LRT has gained particular relevance to prevent tumor progression while patients are on the waitlist, or to downstage tumors to meet transplantability criteria.[8,9]

On the other hand, the eff i cacy of LRT in improving long-term patient survival after liver transplantation remains unclear with only few studies suggesting posttransplant survival benef i t.[10,11]

Radiologic tumor response def i ned by World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), and European Association for the Study of the Liver (EASL) guidelines have been established and can correlate with histopathological necrosis.[12,13]These guidelines contemplate measurement of change in tumor diameter and enhancement in cross sectional imaging such as computed tomography (CT) and magnetic resonance (MR) as a result of LRT.

Despite evolution and different applications of LRT, complete tumor response via analysis in explanted livers is observed in less than 50% of the cases. Similarly, radiologic and histologic correlation is partial, considering that current imaging technology underestimates tumor staging in about 20%-40% of the cases.[14]

The purpose of this study was to evaluate different levels of radiologic response after pre-LT LRT and its correlation with the degree of tumor necrosis on explanted histopathology and its impact on survival among different groups.

Methods

A prospectively maintained Institutional Review Board approved LT database and medical records of consecutive patients who underwent LT for HCC in our institution were reviewed. Patients who had undergone LT or died within 6 months of review period were excluded. All patients were seen by a dedicated team of hepatologists, hepatobiliary/LT surgeons, oncologists and interventional radiologists with an interest in HCC. The diagnosis of HCC was made on histological or radiological criteria according to the published guidelines.[15,16]No transplanted patient had evidence of tumor macrovascular invasion or extrahepatic metastatic disease on pre-transplant imaging. LRT decisions were made prior to transplantation based on tumor criteria and liver function. Various therapeutic interventions including RFA, conventional TACE, doxorubicin embolization bead (DEB), bland embolization and Y-90 radioembolization were implemented. Persistent arterial enhancement of tumors that were originally hyper-enhancing or no change in the original tumor density after LRT was considered as an evidence for a residual viable tumor. Tumor response to LRT was evaluated 1 to 3 months via CT or MR after treatment and needs a further treatment based on the determination of the residual viable tumor, whether the patient was considered within or beyond the Milan criteria was based on liver function. Tumor response was classif i ed as complete, partial, no response (unchanged radiologic tumor appearance) or progressive disease. Data were collected in terms of demographics, etiology of underlying liver disease, MELD scores, waitlist time, tumor burden (within or beyond Milan criteria), and locoregional treatments. All pre-transplant imaging reports including imaging studies performed before and after each LRT were reviewed to determine the radiographic characteristics of each HCC by expert abdominal radiologists.

After transplantation, all liver explants were submitted for review by an experienced hepatopathologist. Native livers were serially sectioned, grossly examined, and fi xed in formalin. Representative sections of the nonlesional liver of all lobes were subsequently embedded in paraff i n. The size, location, and gross characteristics of all lesions were recorded. The degree of tumor differentiation (well, moderate, or poor) was graded according to the Edmondson criteria.[17]For purposes of statistical analysis, tumors that demonstrated heterogeneous differentiation were grouped according to the worst histologic grade within the tumor. The percentage of viable tumor was determined by the ratio of estimated viable tumor volume to the entire tumor volume. The pathological response to therapy was graded as complete (100% tumor necrosis), partial (51%-99% tumor necrosis) and poor (<50% tumor necrosis).

Statistical analysis

For analysis of continuous factors between two groups, Student'sttest or, if appropriate, nonparametric Wilcoxon's rank-sum test were used, and ANOVA test was used for comparison among multiple groups. Categorical variables were analyzed by Pearson's product-moment correlation coeff i cient, the Chisquare test or Fisher's exact test. Survival analysis was performed using the Kaplan-Meier method, and the logrank test was used to compare the groups. In addition, multivariable proportional hazards regression was performed to adjust potential confounders for assessing the association between the groups. APvalue of <0.05 was considered statistically signif i cant.

Results

Between the period of 2002 and 2011, 174 patientsreceived pre-LT LRT for HCC. Twenty patients were excluded for early postoperative death or inadequate follow-up, and 26 patients without post-LRT imaging before transplantation were excluded. A total of 128 patients who underwent pre-LT LRT with pre- and post-LRT CT or MR imaging were included in the study.

All patients received cadaveric LTs. Their mean age was 58±9 years and 76% of the patients were male. HCV was the main cause of chronic liver disease in 64% of the patients. The median waitlist time until transplant was 55 days, with a mean follow-up period of 35±27 months. MELD score without exception points was 12.6 ±4.5; and there was no signif i cant change in MELD scores after LRT.

One hundred patients (78%) had HCC within the Milan criteria and 28 patients (22%) had HCC beyond the Milan criteria at the initial radiologic diagnosis (Table 1).

LRT in the form of TACE was given to 65 (51%) patients, with drug-eluding beads in 15 (12%) patients and bland embolization in 6 (5%) patients. RFA was performed in 20 (16%) patients. Transarterial radioembolization with Y-90 was performed in 7 (5%) patients.

Overall, 96 (75%) patients received only one session of therapy, 22 (17%) received 2 sessions, and 10 (8%) received 3 or more sessions.

The 1-, 3- and 5-year post-transplant overall survival rates in the entire cohort were 93%, 82% and 74%, respectively. Disease free survival at 1, 3 and 5 years was 92%, 80% and 72%, respectively. There was no signif i cant difference in overall survival (P=0.4) or recurrence free survival (P=0.1) between patients presenting with HCC within or beyond the Milan criteria (Figs. 1, 2).

After a mean follow-up of 35 months, 27 (21%) patients died, of whom 23 (18%) were due to tumor recurrence. The mean time to recurrence was 22.2± 3.2 months. Tumor recurrence was most common inthe liver (8 patients), in the lung (7), in bone (5), and in other sites (3).

Table 1.Patients characteristics

Tumor radiologic characteristics (Table 2)

The mean radiologic tumor size of the largest lesion was 3.2±1.5 cm and the median number of lesions was 2 (range 1-2). As expected, there was a signif i cant difference in the size (P=0.0001) and number of lesions(P=0.0001) between patients within and beyond the Milan criteria.

Fig. 1.Overall survival for patients within and beyond Milan criteria.

Fig. 2.Recurrence free survival for patients within and beyond Milan criteria.

Table 2.Radiological characteristics of patients receiving LRT

A complete radiological response was seen in 50 (39%) patients, partial radiologic response in 34 (27%), poor or no response in 37 (29%), and progressive disease in 7 (5%). There was no signif i cant difference in radiologic response between patients within or beyond the Milan criteria (P=0.2). Nevertheless, overall and disease free survival rates were signif i cantly better those in the complete vs incomplete radiologic response group (the 3-year overall survival rate was 90% vs 78% (P=0.03) and disease free survival rate was 88% vs 73% (P=0.02).

Histologic characteristics (Table 3)

The mean histologic tumor size of the largest lesions was 3.2±1.7 cm, and the median number of lesions was 1 (range 1-3).

Complete tumor necrosis was observed in 19 (15%) patients, partial necrosis in 50 (39%), and poor or no necrosis in 52 (41%), and 7 (5%) progressive disease. There was no signif i cant difference in necrosis rate between patients within or beyond the Milan criteria (P=0.4).

Table 4 shows the rate of tumor necrosis by type of LRT. In the 19 patients, complete tumor necrosis was treated by TACE and DEB in 14 (74%), by Y-90 radioembolization in 2 (10.5%), by RFA in 1 (5%), and by combination of therapies in 2 (10.5%). Complete tumor necrosis rate was higher in the TACE/DEB group (51%) than in the groups treated by Y-90 radioembolization (29%), TACE (15%), and combined therapy (15%).

Univariate analysis showed that a low number of lesions (P=0.009) and complete radiologic response (P=0.002) were associated with complete tumor necrosis. Patients with HCC within the Milan Criteria (P=0.09) who received chemoembolization and exhibited well tumor differentiation (P=0.07) had a higher rate of complete tumor necrosis; however, this was not statistically signif i cant (Table 5). Multivariate analysis showed no association between complete tumor necrosis and the mentioned variables.

There was a signif i cant difference in overall (P=0.02) and recurrence free survival (P=0.001) regarding histopathologic tumor necrosis rates (complete, partial or no/poor) (Figs. 3, 4). Patients with complete tumor necrosis were associated with best survival (P=0.02).

Radiologic and histologic correlation (Table 6)

The median time between last CT/MR to LT was 31 days. There was a signif i cant difference in tumor staging between the last CT/MR before LT and explant histopathologic evaluation in regard to the number and size of lesions (P=0.01).

After LRT under radiologic evaluation, there were 117 patients within the Milan criteria and only 11 patients beyond the Milan criteria; however, after histopathologic evaluation there were 94 patientswithin the Milan criteria versus 34 patients beyond the Milan criteria (P=0.01). In addition, of 50 patients who exhibited complete radiologic response, only 15 (30%) patients showed complete tumor necrosis by histopathologic evaluation.

Table 3.Histological characteristics of patients received LRT

Table 4.Histologic necrosis by type of LRT (n, %)

Table 5.Analysis of patients by pathological response

Fig. 3.Overall survival by necrosis response.

Fig. 4.Recurrence free survival by necrosis response.

Fig. 5.Overall survival of downstaged vs non-downstaged patients.

Fig. 6.Recurrence free survival of downstaged vs non-downstaged patients.

Table 6.Correlation of CT/MRI before LT and histopathological evaluation

Overall pre-LT radiologic staging was correlated with explant pathology in 73 (57%) patients. It underestimated tumor stage in 49 (38%) patients, and overestimated tumor stage in 6 (5%).

Downstaging

Twenty-eight patients who were beyond the Milan criteria at initial radiologic diagnosis received LRT. Seventeen (61%) patients were radiologically downstaged to the Milan criteria after treatment and 11 (39%) patients failed to be downstaged. From the 17 patients who were downstaged, only 6 (35%) patients achieved complete radiologic response.

The overall survival rates at 1 and 3 years in the downstaged group versus the non-downstaged group versus the within Milan criteria group at presentation were 93%, 93% vs 81%, 61% vs 94%, 84%, and the recurrence free survival rates were 93%, 93% vs 72%, 39% vs 92%, 81%, respectively.

There was a signif i cant difference in overall (P=0.05) and recurrence free survival (P=0.01) between the downstaged and non-downstaged patients (Figs. 5, 6). When we compared patients downstaged to the Milan criteria with those within the Milan criteria at presentation, there was no signif i cant difference in overall (P=0.7) and recurrence free survival (P=0.6) (Figs. 7, 8).

Fig. 7.Overall survival of patients downstaged vs patients within the Milan criteria at presentation.

Fig. 8.Recurrence free survival for patients downstaged vs patients within the Milan criteria at presentation.

Discussion

LT is a possible curative treatment for HCC. In addition to overcome chronic organ disease and its carcinogenic potential, it can completely eradicate HCC isolated to the liver.[18,19]Large experience has demonstrated and validated the eff i cacy of LT for tumors within the Milan criteria (def i ned as no gross vascular invasion with either a single tumor less than or equal to 5 cm or 3 tumors with largest lesion less than 3 cm).[18-21]In contrast, the results of LT for larger tumors have been varied from good to poor outcomes.[22-24]

LTs in the form of RFA, ethanol injection and transarterial therapies including chemo- or blandembolization, or radioembolization have been utilized to treat HCC in both transplant and non-transplant settings.[10,11]In patients awaiting LT, the rationale of utilizing LRT is to prevent tumor progression and waitlist drop out, and to determine tumor biology by evaluating response to treatment. In line with this, interpretation of radiologic response to LRT has become important in the management of patients with HCC who are considered for transplantation.

While in non-transplant candidates, TACE was associated with survival benef i t,[25]and RFA showed it can be correlated with similar outcomes as surgical resection for small HCC;[26]the eff i cacy of LRT in improving long-term patient survival after LT remains unclear. Nevertheless, successfully downstaged tumors are correlated with better post-transplant outcome than tumors that failed downstaging.[8,25]In line with this, a "treat and wait" approach for patients with HCC beyond the Milan criteria has been adopted by transplant centers to def i ne transplant candidacy in high risk patients.[26,27]This approach entails observing tumor behavior for a period of about 3 months after LRT. If tumor remains downstaged during the period of observation, patients are then selected for transplantation assuming a more favorable biology.

Interpretation of tumor response to treatment via LRT has been def i ned by different off i cial guidelines including WHO, RECIST, EASL and modif i ed RECIST.[28,29]Basically these consider changes in size, number and enhancement of HCC as a result of LRT. Typically, absolute absence of enhancement in a previously enhancing HCC would be considered as a complete tumor response.[28]Unfortunately, due to the nature of different LRT, the radiologic appearance of HCC after treatment may vary, thus making radiologic interpretations challenging. That is particularly the case of HCC receiving radioembolization, where due to the radiation effect, radiologic interpretation of tumor response could be diff i cult during the fi rst 6 months after treatment.[12]Similarly, HCC can vary in its radiologic appearance including well def i ned enhancing lesions, more diffuse inf i ltrative patterns and less enhancing, making radiologic interpretation of tumor response to therapy complicated.[16]Overall, studies on radiologic and histologic correlation show that current cross sectional imaging like CT or MR underestimates tumor stage in 20%-40% of cases.[14]

In a previous publication from our center, we presented our experience with 225 patients undergoing transplantation with the Milan criteria HCC, and with 93 patients receiving pre-transplant LRT. This study suggested that LRT followed by LT in Milan criteria HCC patients with short waitlist time does not appear to affect post-transplant outcomes.[14]In the present study, data from 128 patients were retrospectively analyzed. We specif i cally investigated the radiologic response to pre-LT LRT in HCC patients within and beyond the Milan criteria, and its correlation with percentage of tumor necrosis on explanted histopathology, and its impact on post-transplant outcome.

Overall, patients tolerated LRT well without a signif i cant increase in MELD scores after treatment (P=0.5). A 17% post-transplant tumor recurrence rate was noticed after a mean follow-up of nearly 3 years. The overall survival rate at 1, 3 and 5 years for the entire cohort was 93%, 82% and 74%, respectively; and the diseasefree survival rate at 1, 3 and 5 years was 92%, 80% and 72%, respectively.

While there was no signif i cant difference after LRT in overall survival (P=0.4) or recurrence free survival (P=0.1) between patients beyond or within the Milan criteria at presentation, a signif i cant difference in survival was noticed between patients who were successfully downstaged and those who were not (Figs. 5, 6). In line with this, similar results have been reported by Majno et al.[25]They found that among 57 patients with one or more tumors ≥3 cm, 19 patients achieved notable tumor downstaging after LRT and subsequently had a considerably better 5-year recurrence free survival (71% vs 49%) than those who did not receive LRT or did not respond (71% vs 29%) to therapy. Similarly, Yu el al[30]studied 51 HCC patients who were successfully downstaged within the Milan criteria after LRT. It was concluded that downstaged patients who were transplanted showed excellent tumor-free and overall survival rates, similar to those of the patients who were originally within the Milan criteria.[30]

The ideal goal of LRT is to induce total tumor necrosis. In our study, histopathologic analysis indicated that 19 (15%) patients had complete tumor necrosis induced by LRT. This group of patients exhibited a 5-year recurrence free survival rate of 100%. But previous studies[10,27]showed that the occurrence of more than 60% tumor necrosis has been associated with an increase in disease free survival.

When different modalities of LRT were used, complete tumor necrosis was noticed commonly in the TACE/ DEB group (51%) followed by the Y-90 group (29%) and the combined therapy group (15%). A larger number of treatments in each group would be needed to determine if one modality is superior. In addition, there is more than one particular eff i ciency to induce total tumor necrosis by a specif i c type of therapy. These results may ref l ect bias since most of the patients receiving radioembolization had multifocal HCC, but most of the patients with unifocal tumors received DEB therapy.

Univariate analysis showed that a low number of lesions and complete radiologic response were associated with complete tumor necrosis; however none of these factors were shown to be signif i cant on multivariate analysis. This discordant analysis could be attributed to the small sample size.

Imaging technology may need improvement in def i ning patterns of tumor vascularity and scales of enhancement that correlate better with the presence of tumor viability or necrosis. In our group, we found that hypervascular lesions are associated with a higher rate of tumor necrosis as a result of LRT. Kwan et al[31]studied 132 HCC lesions in patients who underwent LT after TACE. They found that avid contrast enhancing HCC lesions, a feeding artery size larger than 0.9 mm, absence of residual enhancement and an extensive accumulation of ethiodized oil in the tumor, are associated with nearcomplete tumor necrosis upon histopathologic analysis after TACE. These fi ndings may help to guide the selection of an optimal treatment strategy for HCC's with different patterns of radiological appearance.

Our study has certain limitations. Although our transplantation database is maintained prospectively, this report represents a retrospective review of nearly 9 years. During this period, different physicians have intervened in the decision-making and performance of LRT. Besides, changes in technology of LRT and in imaging scanners have occurred over this time.

However, as validated by other reports, our study can educate us in that LRT can be a valid option to downstage and prevent tumor progression in patients awaiting LT. In addition, pre-LT LRT appears to be a legitimate tool to determine tumor biology by evaluating response to treatment and therefore useful in selecting LT for high-risk patients. Additionally, although larger experience is needed, this study demonstrates that patients with complete tumor necrosis after LRT have an excellent long-term survival rate. Despite evolution of imaging technology, however, there is a considerable discrepancy between radiology and histology. In conclusion, LRT has evolved into a pivotal instrument to manage patients with HCC awaiting LT. In the near future, evolution in imaging and LRT technology may have a def i nitive impact on post-transplant outcome.

Contributors:EG proposed the study, wrote the fi rst draft and analyzed the data. All authors contribute to design, interpretation and reviewing the study and further drafts. EG is the guarantor.

Funding:None.

Ethical approval:This study was approved by the Institute Review Board.

Competing interest:No benef i ts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received November 28, 2012

Accepted after revision January 1, 2013

Federico Aucejo, MD, Euclid Avenue, A100, Cleveland Clinic Foundation, Cleveland, OH 44120, USA (Email: aucejof@ccf.org)

10.1016/S1499-3872(13)60003-X

AuthorAff i liations:Hepatobiliary & Liver Transplant Surgery, Cleveland Clinic Foundation, Cleveland, OH 44120, USA (El-Gazzaz G, Sourianarayanane A, Menon KVN, Sanabria J, Hashimoto K, Quintini C, Kelly D, Eghtesad B, Miller C, Fung J and Aucejo F)

This paper has been accepted as a podium presentation atAmerican Transplant Congress-2011.

? 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.