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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

There is increasing evidence that a relevant number of patients with hepatocellular carcinoma (HCC) exceeding the Milan criteria may benefit from liver transplantation (LT). We retrospectively analyzed the prognostic significance of [18F]fludeoxyglucose ([18F]FDG) positron emission tomography (PET) for identifying appropriate LT candidates with advanced HCC on clinical staging. Between 1995 and 2008, 111 patients with HCC were listed for LT. All underwent a pretransplant PET evaluation. LT was performed for 91 of these patients. The tumor recurrence rate after LT was 3.6% for patients with non–[18F]FDG-avid (PET) tumors, but it was 54.3% for patients with [18F]FDG-avid (PET+) tumors (P < 0.001). The 5-year recurrence-free survival rates were comparable for patients with tumors meeting the Milan criteria (86.2%) and patients with PET HCC exceeding the Milan criteria (81%) at LT, but these rates were significantly higher than the rate for liver recipients with [18F]FDG-avid advanced HCC (21%, P = 0.002). In a multivariate analysis, negative PET findings (odds ratio = 21.6, P < 0.001), an alpha-fetoprotein level <400 IU/mL (odds ratio = 3.3, P = 0.013), and a total tumor diameter <10 cm (odds ratio = 3.0, P = 0.022) were identified as pretransplant prognostic variables for recurrence-free survival. A PET+ status was assessed as the only independent clinical predictor of tumor-related patient dropout from the waiting list (hazard ratio = 5.7, P = 0.01). Patients with non–[18F]FDG-avid HCC beyond the Milan criteria according to clinical staging may achieve excellent long-term recurrence-free survival after LT. Liver Transpl 18:53–61, 2012. © 2011 AASLD.

The adoption of the restrictive Milan criteria [a solitary hepatocellular carcinoma (HCC) tumor up to 5 cm in diameter or as many as 3 HCC nodules with a maximum diameter of 3 cm without macrovascular infiltration] has significantly improved the prognosis of patients with HCC after liver transplantation (LT).1, 2 The number of LT procedures performed for HCC has been steadily increasing. In recent years, however, concerns have been raised: the Milan criteria may be too restrictive, and many patients with advanced HCC who have an acceptable prognosis are being excluded from curative LT.3, 4 This has prompted several proposals for more liberal selection criteria, and most are based on macromorphological imaging results.5-7 There is increasing evidence that a tumor's biology, rather than its macromorphology, is associated with outcomes after LT for patients with advanced HCC. However, biological features of tumor aggressiveness, including a poor tumor grade and microscopic vascular invasion (MVI), are not routinely available before transplantation and may change in the context of interventional bridging therapies.8, 9

The uptake of [18F]fludeoxyglucose ([18F]FDG) on positron emission tomography (PET) scans, which is based on enhanced glucose metabolism in cancer cells, is a sensitive and noninvasive biological marker for assessing metabolic tumor viability. [18F]FDG PET is nowadays a well-established diagnostic tool for the evaluation and treatment monitoring of a variety of malignant tumors.10, 11 It is less suitable for the primary detection of HCC but has some prognostic value after liver resection.12-14 Recently, it has been demonstrated that enhanced preoperative [18F]FDG uptake correlates with histological parameters of tumor aggressiveness in the transplant setting.15-17 There are, however, no data about the value of pretransplant PET for identifying appropriate LT candidates with advanced HCC on clinical staging.

We, therefore, conducted a retrospective analysis to evaluate the prognostic significance of enhanced glucose metabolism on PET scans in a series of LT candidates with HCC beyond the Milan criteria on medical imaging.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Characteristics

From January 1995 to December 2008, 111 patients with HCC were listed for LT at our center (Table 1). Data were collected in a prospective database and retrospectively analyzed.

Table 1. Characteristics of All Patients Listed for LT (n = 111)
VariableValue
  • *

    Sixty-eight patients underwent interventional bridging therapy.

Age (years) 
 Mean ± standard deviation59.0 ± 6.9
 Range38-71
Sex (n) 
 Male67
 Female44
Etiology of liver disease (n) 
 Alcoholic60
 Viral32
 Cholestatic3
 Metabolic10
 Autoimmune5
 Hemochromatosis1
Child class at listing (n) 
 A45
 B37
 C29
Interventional therapy before LT (n)* 
 TACE60
 RFA8
PET staging before LT 
 Non–[18F]FDG-avid65
 [18F]FDG-avid46

Pretransplant clinical staging included preoperative and intraoperative ultrasonography, dynamic computed tomography (CT), and contrast-enhanced magnetic resonance tomography. Furthermore, whole-body [18F]FDG PET was performed for all patients at least once before LT. We did not routinely perform preoperative tumor biopsy.

At the time of listing, the tumors of all study patients met the Milan criteria according to radiographic staging.1 Pretransplant clinical tumor progression (with respect to the size and number of HCC tumors on radiography) did not result in patient dropout per protocol. Patients were removed from the waiting list for relevant biological tumor progression (ie, tumor invasion into a major vascular branch, lymph node metastases, extrahepatic tumor spread, or tumor-related symptoms).

Alpha-fetoprotein (AFP) measurements and abdominal ultrasound examinations were performed every 3 months, whereas cross-sectional imaging was performed at least every 6 months and in the case of significantly increased AFP levels.

Since 1999, LT candidates underwent transarterial chemoembolization (TACE) or percutaneous radiofrequency ablation (RFA) for their tumors if they were eligible for technical and/or functional reasons. Surgical resection was not considered standard bridging therapy before LT. The response to neoadjuvant therapy was determined with contrast CT scanning. The viable tumor volume was defined by contrast agent uptake in the arterial phase and washout in the portal venous and late venous phases.18, 19 Only the viable tumor volume was used for macromorphological staging.

All staging results were based on pretransplant medical imaging (not explant histopathology).

The immunosuppressive therapy consisted of a calcineurin inhibitor–based induction regimen that was augmented by mycophenolate mofetil or azathioprine. Except for patients with autoimmune hepatitis, steroids were tapered off at most 6 months after LT.

The posttransplant tumor surveillance consisted of AFP measurements and abdominal ultrasound examinations every 3 months and CT scans of the chest and abdomen every 6 months.

Histopathology

All explanted livers were histopathologically examined by 2 experienced pathologists who determined the size, number, total tumor diameter, stage, and vascular invasion status. Tumor differentiation was determined according to Edmondson and Steiner's grading system. Surgical and pathology staff cooperated on histopathological tumor staging, which was based on clinical and pathological data and was determined according to the 1997 edition of the tumor-node-metastasis criteria of the International Union Against Cancer.20 Furthermore, tumors were classified according to the Milan and University of California San Francisco (UCSF) criteria.1, 7

[18F]FDG PET

Pretransplant [18F]FDG PET was performed with an ECAT EXACT 47 scanner (Siemens, Erlangen, Germany); the whole-body mode was implemented as standard software. Patients fasted for at least 8 hours before PET scanning. A static emission scan was performed 60 to 90 minutes after the injection of approximately 360 MBq of [18F]FDG from the neck to the knee level in a 2-dimensional mode. The PET scans were correlated with the corresponding CT scans for accurate tumor localization. In recent years, an integrated PET/CT scan was performed. Two specialists in nuclear medicine evaluated the coronal, sagittal, and axial PET images. The [18F]FDG tumor uptake was assessed semiquantitatively through the determination of the tumor/background (T/B) ratio, as previously described.14-17 A T/B ratio > 1 indicated enhanced [18F]FDG uptake in the tumor ([18F]FDG-avid or PET+; Fig. 1). In contrast, a T/B ratio of 1 identified HCCs without suspicious glucose metabolism on a PET scan (non–[18F]FDG-avid or PET) in comparison with surrounding noncancerous hepatic tissue.

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Figure 1. PET/CT scan revealing [18F]FDG-avid HCC in the right liver.

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Pretransplant Prognostic Variables

In order to identify pretransplant prognostic parameters, the following variables were included in univariate and multivariate analyses: donor and recipient ages, sex, AFP levels, number and size of tumor nodules on final pretransplant radiographic staging, responses to interventional bridging therapies on CT scans, Milan/UCSF status according to the final pre-LT clinical staging, and PET status for HCC.

Statistical Analysis

All analyses were performed with the statistical software SPSS 17.0 for Windows. Correlations of clinical and histopathological variables with frequencies of tumor recurrence and tumor-related dropout from the waiting list were analyzed with χ2 tests and logistic regression. The analysis of recurrence-free survival was performed according to the Kaplan-Meier method. Patient survival rates in different groups were compared with the log-rank test. Variables with a significant prognostic impact in a univariate analysis (P < 0.05) were entered into a stepwise multivariate analysis that used a Cox multiple stepwise regression model.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient and Tumor Characteristics

Finally, 91 patients underwent LT. There were 60 male patients and 31 female patients. The mean recipient age was 58.3 ± 7 years at LT. Seventy-eight patients underwent LT with deceased donors, whereas 13 patients underwent LT with living donors. Both procedures were performed with standard techniques as previously described.21

According to the final preoperative clinical staging, 57 patients satisfied the Milan criteria (62.6%), whereas the tumor burden exceeded the Milan criteria in 34 patients (37.4%; Table 2). In 27 patients (29.7%), the tumors were determined to be beyond the UCSF criteria (a tumor lesion ≤ 6.5 cm or 2-3 lesions ≤ 4.5 cm with a total tumor diameter ≤ 8 cm and an absence of gross portal vein invasion) at LT.7

Table 2. Clinical Parameters According to Pretransplant Staging and Histopathological Parameters at Explantation for Liver Recipients (n = 91)
Clinical Parameters
VariablePatients Within the Milan CriteriaPatients Outside the Milan CriteriaP Value
Total patients (n)5734 
AFP level (n)  0.01
 ≤400 ng/mL5426 
 >400 ng/mL38 
Pretransplant treatment (n)  0.31
 None2014 
 TACE3019 
 RFA71 
Radiographic imaging   
 Mean number of tumor nodules1.42.9<0.001
 Mean maximum diameter of largest tumor nodule (cm)3.16.1<0.001
 Total tumor diameter (cm)4.110.1<0.001
Response to bridging therapy  0.015
 Yes278 
 No1012 
PET staging before LT  0.002
 Non–[18F]FDG-avid4214 
 [18F]FDG-avid1520 
Histopathological Parameters
VariablePatients Within the Milan CriteriaPatients Outside the Milan CriteriaP Value
Total patients (n)5734 
Tumor differentiation  0.141
 Good/moderate4925 
 Poor89 
Microvascular invasion1522<0.001
Major vascular invasion310.601
Lymphatic vascular invasion1070.719

As expected, patients within the Milan criteria had fewer HCCs, smaller dominant HCC nodules, and lower total tumor diameters on pretransplant clinical staging (P < 0.05; Table 2). In addition, in comparison with patients within the Milan criteria (15/57 or 26.3%), more patients with tumors outside the Milan criteria (20/34 or 58.8%) demonstrated enhanced glucose metabolism on pretransplant PET scans (P = 0.002; Table 2).

Responses to interventional bridging therapies were noted in 27 patients within the Milan criteria (73%) and in 8 recipients outside the Milan criteria (40%, P = 0.015; Table 2).

According to explant histopathology, there were more tumors with MVI in recipients outside the Milan criteria versus patients within the Milan criteria (P < 0.001). Furthermore, we noticed a trend of more high-grade HCCs in patients outside the Milan criteria (P = 0.141; Table 2).

PET Characteristics and Parameters of Tumor Biology

[18F]FDG PET scans were performed for all patients 1.5 to 15 months (median = 6 months) before LT and before the initiation of interventional bridging therapies.

Thirty-five liver recipients had positive preoperative PET scans (38.5%; Fig. 1), whereas the pretransplant PET findings were negative for 56 LT patients (61.5%).

The PET findings were associated with several parameters of pretransplant tumor staging, including the Milan/UCSF status on radiography, responses to bridging therapies on CT scans, and (by tendency) AFP levels at LT (Table 3). Furthermore, a PET+ status was significantly associated with explant histopathology parameters of aggressive tumor behavior, including MVI, grading, and lymphovascular invasion (P < 0.05; Table 3). Only 2 of 56 PET patients (3.6%) developed posttransplant tumor recurrence, but 19 of 35 PET+ recipients (54.3%) did (P < 0.001; Table 3).

Table 3. PET Status and Tumor Characteristics of Liver Recipients (n = 91)
Tumor VariablePET+ Status (n = 35)PET Status (n = 56)P Value
  • *

    Fifty-seven patients underwent pre-LT interventional therapy.

AFP level at LT (n)  0.07
 ≤400 U/L2852 
 >400 U/L74 
Response to bridging therapy (n)*  0.002
 Yes525 
 No128 
Milan status (n)  0.002
 Within1542 
 Outside2014 
UCSF status (n)  0.002
 Within1846 
 Outside1710 
Grading (n)  <0.001
 Good/moderate2252 
 Poor134 
Microvascular invasion (n)  <0.001
 No549 
 Yes307 
Lymphovascular invasion (n)  0.014
 No2450 
 Yes116 
Tumor recurrence (n)  <0.001
 No1654 
 Yes192 

Recurrence-Free Survival

The mean posttransplant follow-up was 65.1 ± 44.9 months (range = 5-165 months). The overall and 5-year recurrence-free survival rates for the entire study population were 75.5% and 72.7%, respectively.

The 5-year recurrence-free survival rate was 86.2% for patients within the Milan criteria and 47.4% for patients outside the Milan criteria (P < 0.001).

There was no survival difference between patients receiving neoadjuvant interventions and those not receiving pre-LT treatments (76% versus 68%, P = 0.31). However, the outcomes were significantly better for progression-free responders (93%) versus nonresponders to interventional bridging therapy (49%, P = 0.004).

PET patients outside the Milan criteria had a 5-year recurrence-free survival rate (81%) that was comparable to the rate for recipients within the Milan criteria (86.2%), but it was significantly higher than the rate for PET+ patients outside the Milan criteria (21%, P = 0.002; Fig. 2).

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Figure 2. Patients with non–[18F]FDG-avid HCC exceeding the Milan criteria had a 5-year recurrence-free survival rate (81%) that was comparable to the rate for recipients with HCC within the Milan criteria (86.2%) but was significantly higher than the rate for patients with [18F]FDG-avid HCC outside the Milan criteria (21%, P = 0.002).

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There was no significant difference in the 5-year recurrence-free survival rates for patients meeting the UCSF criteria [85% (n = 64)] and PET patients exceeding the UCSF criteria [85.7% (n = 10)], whereas the outcomes were significantly worse for patients with [18F]FDG-avid HCC beyond the UCSF criteria [19.2% (n = 17), P = 0.001; Fig. 3].

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Figure 3. The 5-year recurrence-free survival rates for patients with tumors meeting the UCSF criteria and patients with PET HCC exceeding the UCSF criteria were comparable but were significantly higher than the rate for patients with PET+ HCC beyond the UCSF criteria (P = 0.001).

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In the univariate analysis, an AFP level <400 IU/mL, fewer than 3 tumor nodules, a dominant nodule diameter <5 cm, a total tumor diameter <10 cm, a tumor stage meeting the Milan criteria, and negative PET findings were associated with posttransplant recurrence-free survival (P < 0.05; Table 4). In the multivariate analysis, a PET status, an AFP level <400 IU/mL, and a total tumor diameter <10 cm were identified as independent predictors of recurrence-free survival (P < 0.05; Table 4). Notably, the parameters defining the Milan criteria were not significantly associated with outcomes in the multivariate analysis.

Table 4. Univariate and Multivariate Analyses of Pretransplant Predictive Parameters for Liver Recipients (n = 91)
Univariate Analysis
VariableLog-Rank P Value
AFP level ≤ 400 U/L at LT<0.001
Number of tumor nodules ≤ 30.02
Tumor diameter of dominant nodule ≤ 5 cm0.05
Total tumor diameter ≤ 10 cm<0.001
Within the Milan criteria0.002
PET status<0.001
Multivariate Analysis
Variable95% Confidence IntervalOdds RatioP Value
PET status4.9-94.921.6<0.001
AFP level ≤ 400 U/L at LT1.3-8.23.30.013
Total tumor diameter ≤ 10 cm1.2-7.93.00.022

When neoadjuvant therapy was included in the multivariate analysis (n = 57), a PET+ status remained the only independent variable for tumor recurrence.

PET Status and Risk of Patient Dropout

Twenty LT candidates were dropped from the waiting list (18%): 13 for relevant tumor progression and 7 for other complications. The tumor-related dropout rate differed significantly between patients with [18F]FDG-avid HCC (10/46 or 21.7%) and patients with non–[18F]FDG-avid HCC (3/65 or 4.6%, P = 0.006). Among clinical parameters, only a PET+ status (hazard ratio = 5.7, confidence interval = 1.5-22.2, P = 0.01) was identified as an independent predictor of tumor-related patient dropout from the waiting list (Table 5).

Table 5. Univariate and Multivariate Analyses of Pretransplant Parameters Predicting Tumor-Related Dropout for All Listed Patients (n = 111)
Univariate Analysis
VariableP Value
AFP level > 400 U/L at LT< 0.001
Number of tumor nodules > 30.02
Tumor diameter of dominant nodule > 5 cm0.05
Total tumor diameter > 10 cm0.001
Outside the Milan criteria0.002
PET+ status<0.001
Multivariate Analysis
Variable95% Confidence IntervalHazard RatioP Value
PET+ status1.5-22.25.70.01

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

To our knowledge, we are presenting the largest study conducted so far for the evaluation of the prognostic significance of [18F]FDG PET in the LT setting. We have demonstrated that patients with non–[18F]FDG-avid HCC exceeding the Milan or UCSF criteria on pretransplant clinical staging may achieve an extraordinary 5-year recurrence-free survival rate greater than 80% after LT. A notable observation of our trial is that radiographic tumor progression beyond the Milan criteria while a patient is waiting for LT does not need to instantly result in dropout from the waiting list. Furthermore, we have been able to show that a PET+ status is an independent predictor of tumor-related dropout from the waiting list; this is another important result of our study.

[18F]FDG is a glucose analogue that competes with glucose at transport sites on the cell membrane and in a variety of intracellular enzymatic pathways. Because of different enzymatic activities, well-differentiated HCCs may resemble normal liver tissue, whereas poorly differentiated HCCs may be visualized as hot spots on PET scans.10-13, 22 The sensitivity of [18F]FDG PET is, therefore, low for the primary detection of HCC in comparison with many other cancers.12, 13, 22 In recent years, it has been increasingly used for the evaluation of biological tumor behavior in the setting of conventional surgery and palliative treatment.13, 14, 23 Apart from that, PET seems to have some value for the detection of extrahepatic metastases and posttransplant HCC recurrence.24, 25

Yang et al.15 from the Seoul transplant center were the first to propose PET imaging as a useful preoperative tool for estimating the risk of posttransplant tumor recurrence in patients with HCC. Recently, they were able to confirm these early data with quantitative fludeoxyglucose uptake measurements.17 However, in comparison with our study, the overall number of patients in this follow-up trial was considerably smaller (n = 59), and the mean posttransplant follow-up was significantly shorter (29 ± 17 months). Furthermore, we have analyzed the prognostic value of PET in the context of pretransplant clinical staging and not in the context of parameters available after transplantation (eg, histopathological features).

The results of our trial have to be discussed with caution. On the one hand, they confirm the importance of a restrictive selection process based on macromorphological tumor staging.1, 2 The outcomes were excellent for patients within the Milan criteria and for patients within the UCSF criteria in our study (Figs. 2 and 3). However, the adoption of the Milan/UCSF criteria was recently shown to not completely eliminate the risk of aggressive tumor features and, therefore, to increase the risk of posttransplant tumor recurrence.1, 26 Among our patients within the Milan criteria (n = 57), none of the 42 PET patients (0%) and 7 of the 15 PET+ recipients (46.7%, P < 0.001) developed post-LT HCC recurrence. This interesting result illustrates the prognostic power of PET for identifying early-stage HCC with aggressive biological behavior. However, whether enhanced glucose metabolism on PET scans justifies patient dropout (even though standard selection criteria are fulfilled) remains a matter of critical debate. This controversial issue has to be further evaluated with a larger number of patients.

On the other hand, the results of our study clearly demonstrate that a stringent selection policy will significantly increase the risk of excluding appropriate LT candidates with advanced HCC. Approximately 20% of our study patients would have been excluded from a curative treatment if macromorphological tumor progression beyond the Milan criteria had been a dropout criterion by protocol in our series. Furthermore, the inaccuracy of clinical staging remains a critical issue in this context.26, 27 In our series, 33% of the patients were understaged by final pretransplant medical imaging. Other centers have reported similar findings; clinical imaging alone inaccurately stages 30% to 40% of patients undergoing LT for HCC.26-28 This may be a specific problem for patients who are presenting with borderline tumor stages, especially when both listing and dropout are associated with the Milan criteria.26 Hence, our waiting-list policy is mainly based on the tumor biology rather than the static macromorphology of HCC. Similarly to other major centers,29 we have adopted the Milan criteria for patient listing, but patient dropout is related to relevant biological tumor progression, including extrahepatic tumor spread, invasion into a major vascular branch, and tumor-related symptoms. It seems obvious that the number of patients benefiting from LT will rise in this context; however, the price is an increasing risk of tumor recurrence in others. Thus, the responsible application of such an innovative waiting-list policy urgently requires the implementation of powerful clinical parameters of tumor biology.

The current study provides some good evidence for the ability of PET to describe the biological activity of HCC in the transplant setting. First, the predictive value of a PET status for excluding aggressive histopathological features was very high in our series (Table 3). It has been recently shown that the posttransplant outcomes of patients with advanced HCC may be significantly improved by the exclusion of patients with poor tumor grades, MVI, and high DNA.20-34 However, these data are not routinely available before LT because preoperative fine-needle biopsy results have been shown to poorly correlate with explant pathology results.35 Furthermore, tumor sampling errors and the theoretical risk of tumor spread are additional critical issues of preoperative tumor biopsy.35 In contrast, PET scanning is a noninvasive tool available before transplantation without dangerous adverse effects. Second, the rate of progression-free interventional therapy was significantly higher for patients with non–[18F]FDG-avid HCC (75.8%) versus patients with PET+ tumors (29.4%; Table 3). Because pretransplant tumor down-staging by bridging treatments has been shown to describe a favorable biology for advanced HCC,37-41 this interesting result seems to be another indication of the prognostic value of PET in the transplant setting. Furthermore, we have identified the PET status as the only pretransplant parameter able to independently predict tumor-related patient dropout from the waiting list. To our knowledge, this interesting correlation has not been described before. It has been recently demonstrated that enhanced glucose metabolism on PET scans is closely related to genetic markers of proliferative activity in HCC, and this may be a relevant trigger for tumor-related dropout in patients with [18F]FDG-avid HCC.42, 43

There are some limitations to our study. First, the trial was nonrandomized and retrospective. Second, the prognostic significance of a single pretransplant PET scan in the context of different waiting times and locoregional therapies before LT could be limited. Successful interventional therapies probably alter the glucose metabolism on PET scans. However, whether the conversion from a PET+ status to a PET status in the context of interventional bridging treatments indicates a favorable tumor biology and can, therefore, prevent patient dropout cannot be answered by our data because we did not perform repeat PET evaluations by protocol. In order to address this relevant issue, a prospective trial implementing follow-up PET scans in the context of locoregional therapies seems to be mandatory. Furthermore, the PET results of our study may not be representative of the results for other transplant centers. As mentioned previously, tumor-related patient dropout was mainly based on major contraindications, and this may not be feasible for other institutions. However, the application of a waiting-list policy that is more restrictive than ours might limit the prognostic value of pretransplant PET assessments. This has to be further evaluated. Moreover, the sample size might be too small for identifying relevant trends in survival. In contrast, our trial is powered by a long and concise posttransplant follow-up period and the inclusion of a large number of patients with advanced HCC.

In conclusion, we have demonstrated that [18F]FDG PET is a useful metabolic imaging tool for the evaluation of biological tumor behavior in LT candidates with advanced HCC. Patients with non–[18F]FDG-avid HCC exceeding the Milan criteria or even the UCSF criteria on radiography may achieve excellent long-term recurrence-free survival after LT. LT candidates with [18F]FDG-avid HCC should be carefully re-evaluated during the waiting period for LT, and an aggressive down-staging treatment policy should be considered if it is possible. However, whether neoadjuvant bridging therapies can beneficially alter the glucose metabolism on PET scans and, therefore, prevent patient dropout from the waiting list has to be assessed in the future.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: 693-699.
  • 2
    Yoo HY, Patt CH, Geschwind JF, Thuluvath PJ. The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time. J Clin Oncol 2003; 21: 4329-4335.
  • 3
    Toso C, Asthana S, Bigam DL, Shapiro AM, Kneteman NM. Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the Scientific Registry of Transplant Recipients database. Hepatology 2009; 49: 832-838.
  • 4
    Koschny R, Schmidt J, Ganten TM. Beyond Milan criteria—chances and risks of expanding transplantation criteria for HCC patients with liver cirrhosis. Clin Transplant 2009; 23( suppl 21): 49-60.
  • 5
    Marsh JW, Dvorchik I, Bonham CA, Iwatsuki S. Is the pathologic TNM staging for patients with hepatoma predictive of outcome? Cancer 2000; 88: 538-543.
  • 6
    Klintmalm GB. Liver transplantation for hepatocellular carcinoma: a registry report of the impact of tumor characteristics on outcome. Ann Surg 1998; 228: 479-490.
  • 7
    Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001; 33: 1394-1403.
  • 8
    Yao FY. Liver transplantation for hepatocellular carcinoma: beyond the Milan criteria. Am J Transplant 2008; 8: 1982-1989.
  • 9
    Silva MF, Wigg AJ. Current controversies surrounding liver transplantation for hepatocellular carcinoma. J Gastroenterol Hepatol 2010; 25: 1217-1226.
  • 10
    Delbeke D, Martin WH. Positron emission tomography imaging in oncology. Radiol Clin North Am 2001; 39: 883-917.
  • 11
    Jerusalem G, Hustinx R, Beguin Y, Fillet G. The value of positron emission tomography (PET) imaging in disease staging and therapy assessment. Ann Oncol 2002; 13( suppl 4): 227-234.
  • 12
    Okazumi S, Isono K, Enomoto K, Kikuchi T, Ozaki M, Yamamoto H, et al. Evaluation of liver tumors using fluorine-18-fluorodeoxyglucose PET: characterization of tumor and assessment of effect of treatment. J Nucl Med 1992; 33: 333-339.
  • 13
    Hatano E, Ikai I, Higashi T, Teramukai S, Torizuka T, Saga T, et al. Preoperative positron emission tomography with fluorine-18-fluorodeoxyglucose is predictive of prognosis in patients with hepatocellular carcinoma after resection. World J Surg 2006; 30: 1736-1741.
  • 14
    Seo S, Hatano E, Higashi T, Hara T, Tada M, Tamaki N, et al. Fluorine-18 fluorodeoxyglucose positron emission tomography predicts tumor differentiation, P-glycoprotein expression, and outcome after resection in hepatocellular carcinoma. Clin Cancer Res 2007; 13( pt 1): 427-433.
  • 15
    Yang SH, Suh KS, Lee HW, Cho EH, Cho JY, Cho YB, et al. The role of (18)F-FDG-PET imaging for the selection of liver transplantation candidates among hepatocellular carcinoma patients. Liver Transpl 2006; 12: 1655-1660.
  • 16
    Kornberg A, Freesmeyer M, Bärthel E, Jandt K, Katenkamp K, Steenbeck J, et al. 18F-FDG-uptake of hepatocellular carcinoma on PET predicts microvascular tumor invasion in liver transplant patients. Am J Transplant 2009; 9: 592-600.
  • 17
    Lee JW, Paeng JC, Kang KW, Kwon HW, Suh KS, Chung JK, et al. Prediction of tumor recurrence by 18F-FDG PET in liver transplantation for hepatocellular carcinoma. J Nucl Med 2009; 50: 682-687.
  • 18
    Ippolito D, Bonaffini PA, Ratti L, Antolini L, Corso R, Fazio F, Sironi S. Hepatocellular carcinoma treated with transarterial chemoembolization: dynamic perfusion-CT in the assessment of residual tumor. World J Gastroenterol 2010; 16: 5993-6000.
  • 19
    Bargellini I, Vignali C, Cioni R, Petruzzi P, Cicorelli A, Campani D, et al. Hepatocellular carcinoma: CT for tumor response after transarterial chemoembolization in patients exceeding Milan criteria—selection parameter for liver transplantation. Radiology 2010; 255: 289-300.
  • 20
    Sobin LH, Wittekind C, eds. TNM Classification of Malignant Tumors. 5th ed. New York, NY: Wiley; 1997.
  • 21
    Merion RM. Current status and future of liver transplantation. Semin Liver Dis 2010; 30: 411-421.
  • 22
    Dierckx R, Maes A, Peeters M, Van De Wiele C. FDG PET for monitoring response to local and locoregional therapy in HCC and liver metastases. Q J Nucl Med Mol Imaging 2009; 53: 336-342.
  • 23
    Higashi T, Hatano E, Ikai I, Nishii R, Nakamoto Y, Ishizu K, et al. FDG PET as a prognostic predictor in the early post-therapeutic evaluation for unresectable hepatocellular carcinoma. Eur J Nucl Med Mol Imaging 2010; 37: 468-482.
  • 24
    Yen RF, Chen CY, Cheng MF, Wu YW, Shiau YC, Wu K, et al. The diagnostic and prognostic effectiveness of F-18 sodium fluoride PET-CT in detecting bone metastases for hepatocellular carcinoma patients. Nucl Med Commun 2010; 31: 637-645.
  • 25
    Kim YK, Lee KW, Cho SY, Han SS, Kim SH, Kim SK, Park SJ. Usefulness 18F-FDG positron emission tomography/computed tomography for detecting recurrence of hepatocellular carcinoma in posttransplant patients. Liver Transpl 2010; 16: 767-772.
  • 26
    Schwartz ME, D'Amico F, Vitale A, Emre S, Cillo U. Liver transplantation for hepatocellular carcinoma: are the Milan criteria still valid? Eur J Surg Oncol 2008; 34: 256-262.
  • 27
    Shah SA, Tan JC, McGilvray ID, Cattral MS, Cleary SP, Levy GA, et al. Accuracy of staging as a predictor for recurrence after liver transplantation for hepatocellular carcinoma. Transplantation 2006; 81: 1633-1639.
  • 28
    Sotiropoulos GC, Malagó M, Molmenti E, Paul A, Nadalin S, Brokalaki E, et al. Liver transplantation for hepatocellular carcinoma in cirrhosis: is clinical tumor classification before transplantation realistic? Transplantation 2005; 79: 483-487.
  • 29
    Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19: 329-338.
  • 30
    Cillo U, Vitale A, Grigoletto F, Gringeri E, D'Amico F, Valmasoni M, et al. Intention-to-treat analysis of liver transplantation in selected, aggressively treated HCC patients exceeding the Milan criteria. Am J Transplant 2007; 7: 972-981.
  • 31
    DuBay D, Sandroussi C, Sandhu L, Cleary S, Guba M, Cattral MS, et al. Liver transplantation for advanced hepatocellular carcinoma using poor tumor differentiation on biopsy as an exclusion criterion. Ann Surg 2011; 253: 166-172.
  • 32
    Schmidt C, Marsh JW. Molecular signature for HCC: role in predicting outcomes after liver transplant and selection for potential adjuvant treatment. Curr Opin Organ Transplant 2010; 15: 277-282.
  • 33
    Dvorchik I, Schwartz M, Fiel MI, Finkelstein SD, Marsh JW. Fractional allelic imbalance could allow for the development of an equitable transplant selection policy for patients with hepatocellular carcinoma. Liver Transpl 2008; 14: 443-450.
  • 34
    Jonas S, Al-Abadi H, Benckert C, Thelen A, Hippler-Benscheid M, Saribeyoglu K, et al. Prognostic significance of the DNA-index in liver transplantation for hepatocellular carcinoma in cirrhosis. Ann Surg 2009; 250: 1008-1013.
  • 35
    Pawlik TM, Gleisner AL, Anders RA, Assumpcao L, Maley W, Choti MA. Preoperative assessment of hepatocellular carcinoma tumor grade using needle biopsy: implications for transplant eligibility. Ann Surg 2007; 245: 435-442.
  • 36
    Perkins JD. Seeding risk following percutaneous approach to hepatocellular carcinoma. Liver Transpl 2007; 13: 1603.
  • 37
    Jang JW, You CR, Kim CW, Bae SH, Yoon SK, Yoo YK, et al. Benefit of downsizing hepatocellular carcinoma in a liver transplant population. Aliment Pharmacol Ther 2010; 31: 415-423.
  • 38
    Chapman WC, Majella Doyle MB, Stuart JE, Vachharajani N, Crippin JS, Anderson CD, et al. Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation. Ann Surg 2008; 248: 617-625.
  • 39
    Bharat A, Brown DB, Crippin JS, Gould JE, Lowell JA, Shenoy S, et al. Pre-liver transplantation locoregional adjuvant therapy for hepatocellular carcinoma as a strategy to improve longterm survival. J Am Coll Surg 2006; 203: 411-420.
  • 40
    Otto G, Herber S, Heise M, Lohse AW, Mönch C, Bittinger F, et al. Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma. Liver Transpl 2006; 12: 1260-1267.
  • 41
    Yao FY, Hirose R, LaBerge JM, Davern TJ III, Bass NM, Kerlan RK Jr, et al. A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver Transpl 2005; 11: 1505-1514.
  • 42
    Kitamura K, Hatano E, Higashi T, Narita M, Seo S, Nakamoto Y, et al. Proliferative activity in hepatocellular carcinoma is closely correlated with glucose metabolism but not angiogenesis. J Hepatol; doi:10.1016/j.jhep.2011.01.038.
  • 43
    Lee JD, Yun M, Lee JM, Choi Y, Choi YH, Kim JS, et al. Analysis of gene expression profiles of hepatocellular carcinomas with regard to 18F-fluorodeoxyglucose uptake pattern on positron emission tomography. Eur J Nucl Med Mol Imaging 2004; 31: 1621-1630.