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Original Research |
1 Department of Radiology and Center for Imaging Science, Samsung Medical
Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-gu,
Seoul 135-710, Korea.
2 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School
of Medicine, Seoul, Korea.
3 Department of Pathology, Samsung Medical Center, Sungkyunkwan University
School of Medicine, Seoul, Korea.
Received November 22, 2006;
accepted after revision February 28, 2007.
Address correspondence to H. K. Lim
(hklim{at}smc.samsung.co.kr).
Abstract
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MATERIALS AND METHODS. Institutional review board approval and informed consent were waived for this retrospective study. The subjects were 119 patients (102 men, 17 women; mean age, 49.8 years) with unresectable hepatocellular carcinoma who underwent liver transplantation from September 1996 to May 2005 and survived more than 2 months. We evaluated the incidence, imaging features, cumulative disease-free survival rate, and prognosis for recurrence of hepatocellular carcinoma. We examined clinical, therapeutic, and pretransplantation contrast-enhanced CT findings as prognostic factors and analyzed them with multivariate analysis. The median follow-up period was 17.2 months (range, 2.0-102.4 months).
RESULTS. Recurrence was found in 16 (13.4%) of 119 patients and was most frequent in the liver, with no specific pattern. A multivariate stepwise Cox hazard model showed that the presence of portal venous thrombosis, more than 3-cm diameter of the largest tumor, and a viable tumor volume ratio greater than 10% were statistically independent prognostic factors. The 3- and 5-year cumulative disease-free survival rates for the entire cohort were 82.1% and 76.6%, respectively. Despite local therapy for a solitary metastatic lesion, recurrences were common. The mortality rate among patients with recurrent disease was 56.3%.
CONCLUSION. Recurrence of hepatocellular carcinoma after liver transplantation is common, and the prognosis is not favorable. The presence of portal venous thrombosis and tumor size greater than 3 cm on baseline CT are significant risk factors. Aggressive interventional therapy seems to be helpful as a bridge to liver transplantation.
Keywords: CT • hepatocellular carcinoma • liver • liver transplantation • recurrence
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Many investigators [3-18] have reported on the patterns of and prognostic factors for recurrence of hepatocellular carcinoma after liver transplantation. However, the prognostic factors investigated have been focused more on histopathologic and postoperative clinical data than on preoperative radiologic data. We believe that radiologic determination of the likelihood of recurrence of hepatocellular carcinoma after liver transplantation is as important as histopathologic and postoperative clinical determination. Radiologic studies are superior to other techniques in preoperative evaluation of the nature of the disease and prediction of clinical outcome.
The purposes of this study were, first, to elucidate the incidence, cumulative disease-free survival rate, and factors significant in prognosis of recurrence of hepatocellular carcinoma after liver transplantation exclusively on the basis of preoperative clinical and CT features and, second, to evaluate the patterns and prognosis among patients with recurrent tumors.
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2 months) mainly as the result of
perioperative mortality (n = 16). The remaining 119 patients (102
men, 17 women; mean age, 49.8 years; range, 27-68 years), who had a
preoperative diagnosis of hepatocellular carcinoma based on radiologic
findings with postoperative histopathologic confirmation and survived more
than 2 months, were enrolled in the study. Tables
1 and
2 summarize the characteristics
of these patients.
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Imaging Examinations and Follow-up
CT examinations were performed with one of five helical scanners (HiSpeed
CT/i, LightSpeed QX/i, LightSpeed Ultra, LightSpeed 16, GE Healthcare;
Brilliance 40, Philips Medical Systems) with contrast enhancement. A total of
120 mL of nonionic contrast material (300 mg I/mL iopromide, Ultravist 300,
Schering) was administered IV at a rate of 3 mL/s. In the initial period of
this study, fixed imaging-delay times (30, 60-70, and 180 seconds after
initiation of the injection of contrast medium) were used. The bolus-tracking
technique was adopted when it became available. Using a single-detector
helical CT scanner, we obtained images in a craniocaudal direction with a 7-mm
slice thickness and a 7-mm interval. The parameters for the MDCT examination
were 2.5- to 5.0-mm slice thickness and 2.5- to 5.0-mm intervals.
Follow-up CT was performed 1 month and then every 2-4 months after therapy for hepatocellular carcinoma in cases of radiofrequency ablation (n = 26) and percutaneous ethanol injection therapy (n = 2) and every 3-6 months in cases of transcatheter arterial chemoembolization (n = 70) and surgical resection (n = 15). In some cases in which liver transplantation was scheduled, interventional therapy was performed as a bridge to liver transplantation. After liver transplantation, the patients underwent regular follow-up evaluations with alternating liver sonography and liver CT every 4-8 months for detection of intrahepatic recurrences and with chest radiography every 2-4 months for detection of pulmonary metastasis. Image analysis was performed by consensus of two radiologists who used the methods of routine clinical practice.
Diagnosis of Hepatocellular Carcinoma
Pathologic examination of the explanted liver was made by one
hepatopathologist with 26 years of experience. The freshly explanted liver
specimens were sliced serially from top to bottom at 5-mm intervals.
Macroscopically visible treated or untreated neoplastic nodules were evaluated
with microscopy after standard H and E staining. All of these analyses were
conducted with methods used in routine clinical practice. In all cases, one
radiologist conducted radiologic-pathologic correlation on the basis of
pathologic reports to ascertain that the CT diagnoses of hepatocellular
carcinoma were correct.
Liver Transplantation, Surgical Resection, and Interventional Therapy
In cases in which patients chose liver transplantation for the management
of hepatocellular carcinoma, the only contraindication during our study period
was the presence of extrahepatic involvement of hepatocellular carcinoma
(i.e., imaging evidence of distant metastasis or evident tumor thrombus in the
main portal vein or hepatic veins). We did not adhere to the Milan selection
criteria (see Discussion) because we believed that these criteria were too
stringent. Although lymphadenopathy measuring more than 1 cm was found in the
drainage pathway on CT, this finding was not considered a contraindication to
liver transplantation because the finding also can be present in benign
hyperplasia. Selection of the type of liver transplantation depended on the
availability of a living or cadaveric donor for the patient at the time of
surgery. Most patients who chose not to undergo liver transplantation
underwent surgical resection for the management of hepatocellular carcinoma.
The other patients underwent radiofrequency ablation, percutaneous ethanol
injection, and transcatheter arterial chemoembolization. In some cases,
radiofrequency ablation was used as an adjunct to surgical resection.
Analysis of Prognostic Factors
We examined and evaluated various data as potential prognostic factors for
tumor recurrence after liver transplantation. These prognostic factors are
summarized in Table 3. We
evaluated the number, size, and lobar distribution of the tumor, contact
between the hepatic capsule and the tumor, pattern of tumor margin (discrete
or infiltrative), collateral vessels (> 5 mm) due to portal hypertension,
and lymphadenopathy in the drainage pathway on CT. Filling defect only in the
intrahepatic portion of a portal vein (first and second order branches) was
considered portal venous thrombosis regardless of the contrast enhancement of
the thrombus itself. Viable tumor volume ratio after interventional therapy
was assessed as the ratio of viable portion to entire tumor with the following
formula: sum of volumes of portions of tumor exhibiting contrast enhancement
divided by the sum of volumes of the contrast-enhanced portions plus the sum
of volumes of the iodized oil-retained portions in cases of transcatheter
arterial chemoembolization or the volumes of necrotic unenhanced portions in
cases of radiofrequency ablation and percutaneous ethanol injection therapy.
One radiologist using a 2,000 x 2,000 PACS (Centricity, GE Healthcare)
screen with maximum magnification performed the measurements with an area
measuring tool and summation-of-areas technique
[19,
20] on images obtained during
the hepatic arterial phase of the last follow-up CT examination before liver
transplantation. CT analysis for prognostic factors other than volume
measurement was performed in consensus by two abdominal radiologists with 7
and 23 years of experience in liver CT interpretation.
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Statistical Analysis
After review of the follow-up CT scans after liver transplantation, we
assessed the incidence of tumor recurrence and the cumulative disease-free
survival rate. Cumulative disease-free survival rate was estimated with the
Kaplan-Meier method. Significance of the prognostic factors was evaluated by
univariate analysis with a log-rank test. In the log-rank test, representative
values were used to categorize the data for the continuous variables. For
instance, viable tumor volume ratio was categorized in terms of 10% units from
10% to 90%. We tested all values to determine which were significant. If
multiple risk factors proved significant with this test, we performed
multivariate analysis using a stepwise Cox hazards model to search for
independently significant factors. Statistical significance was considered
p < 0.05. Data analyses were performed with SPSS for Windows
(version 11.0, SPSS).
Analysis of Cases with Recurrent Tumors
In cases in which recurrent hepatocellular carcinoma was found after liver
transplantation, we investigated the number and location of the recurrent
tumors, management of the tumors, disease processes after treatment, and
mortality rates.
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Patterns of initial recurrence varied. The distribution of the tumors was disseminated (> 10 foci) in eight patients, multifocal in three patients (one with two foci in the liver, one with three foci in the lung, and one with four foci in the liver and spine), and solitary in five patients (two with a tumor in the liver, two with a lymph node tumor, and one with a tumor in a lung). The organs in which tumors initially presented also were diverse. The liver (n = 11) was the organ most frequently involved initially, followed by lymph nodes (n = 6), lung (n = 4), bone (n = 2, spine and rib), brain (n = 1), abdominal wall (n =1), and skin (n = 1). Only four patients had recurrent tumors confined to the liver at initial diagnosis. The locations of recurrent tumors in the other 12 patients were both intrahepatic and extrahepatic in seven patients and extrahepatic only in five patients.
Disease-Free Survival Rates and Prognostic Factors
Time to development of recurrence ranged from 0.8 to 41.5 months after
liver transplantation. The 1-, 3-, and 5-year cumulative disease-free survival
rates according to the Kaplan-Meier method were 91.4%, 82.1%, and 76.6%,
respectively (Fig. 1). The mean
duration of recurrence-free survival was 83.0 months (95% CI, 73.2-92.7
months).
Univariate analysis with the log-rank test revealed the following
prognostic factors were significant (Table
3): serum 
-fetoprotein level > 100 ng/mL (p =
0.045), Child-Pugh class other than C (p = 0.004) (which means
patients with more advanced cirrhosis fared better than those with
better-compensated disease), presence of intrahepatic portal venous thrombosis
(p = 0.004), presence of more than three tumors (p = 0.030),
greater than 3-cm diameter of largest tumor (p = 0.002), greater than
8-cm sum of tumor diameters (p = 0.022), and viable tumor volume
ratio after interventional therapy greater than 10% of entire tumor volume
(p = 0.030). Multivariate analysis with a stepwise Cox hazard model
revealed the following prognostic factors were independently statistically
significant (Table 4): presence
of intrahepatic portal venous thrombosis, greater than 3-cm diameter of
largest tumor, and viable tumor volume ratio after interventional therapy
greater than 10% of the original tumor.
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Management and Prognosis of Recurrent Hepatocellular Carcinoma
We administered locoregional therapy to five patients with a solitary
recurrent tumor. Radiofrequency ablation was performed on one patient with a
solitary recurrent tumor in the liver. Excision of the metastatic lesion was
performed on two patients, each with a solitary recurrent tumor in the liver
and metastatic lesion in the lung. Two patients with lymph node metastasis
were treated with radiation therapy. The patients with multifocal or
disseminated metastatic lesions underwent systemic chemotherapy or
transcatheter arterial chemoembolization, depending on the distribution of
disease.
Two patients with a single lymph node metastatic lesion had a good response to radiation therapy. They survived for 48.9 months and 7.2 months after liver transplantation (end of study period) without disease progression. The largest dimension of the lymph node lesions decreased from 2.5 to 0.3 cm and from 2.2 to 0.2 cm, respectively, after radiation therapy (Fig. 2A, 2B, 2C, 2D). Three patients with a solitary recurrent tumor in the liver or lung treated with radiofrequency ablation or excision of a metastatic lesion had disease progression in a multifocal or disseminated form. Disease in the patients with multiple recurrent tumors worsened despite systemic chemotherapy or transcatheter arterial chemoembolization. At the end of the study period, one (20%) of five patients with a single recurrent tumor and eight (72.7%) of 11 patients with multiple recurrent tumors had died 6 days-22.6 months after the initial diagnosis of recurrence. The overall mortality rate among the patients with recurrent hepatocellular carcinoma after liver transplantation was 56.3% (9/16). According to the Kaplan-Meier method, the 1- and 2-year survival rates calculated from the time of initial diagnosis of recurrent hepatocellular carcinoma were 44.1% and 29.4%, respectively. The mean and median durations of survival were 13.4 and 7.1 months (95% CI, 7.8-19.0 and 5.5-8.7 months).
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Significant factors for poor prognosis other than the number and size of
the tumors have been reported by many investigators. These factors include
microscopic vascular invasion by the tumor
[3-7],
poor histologic differentiation
[8,
9], presence of a microscopic
peritumoral capsule [10],
presence of partial necrosis of the nodule in the explanted specimen
[11], presence of microscopic
satellite nodules in the explanted specimen
[12], allelic loss of
heterozygosity for various tumor suppressor genes
[13], specific type of
lymphocytic infiltrate to the tumor as immune response
[14], immunosuppressive
regimen after liver transplantation
[15], high preoperative level
of serum -fetoprotein
[16], and advanced TNM stage
[17,
18]. Even though some of these
factors, such as serum -fetoprotein level, are controversial
[10], all but the last two can
be documented only after liver transplantation by use of histopathologic and
genetic analysis of the explanted specimen or of clinical data after liver
transplantation. This problem is especially evident in some centers reluctant
to perform percutaneous biopsy before liver transplantation for fear of tumor
seeding. Prognostic factors related to certain therapeutic techniques have
greater clinical implication when they can be used for prognosis of clinical
outcome before therapy is initiated. This fact adds value to our study, which
dealt with exclusively preoperative data as prognostic factors.
Recurrence of hepatocellular carcinoma after liver transplantation is common, the reported recurrence rate being as high as 40% [2]. However, in cases in which the Milan selection criteria were adopted, risk of recurrence decreased to 10-15% at 5 years [12, 28]. In our study, the cumulative recurrence rate at 5 years was 23.4%, higher than the rates in studies in which the Milan criteria were used. Reviewing our data on the size and number of the tumors, were found that not a few (44/119, 37%) of the cases did not fulfill the Milan selection criteria at the time of transplantation. This finding may be a reasonable explanation for the higher recurrence rate. Recurrence patterns in our study also were not very different from those in previous studies. In our study, the organ most frequently involved initially was the liver; in other studies [10, 17], it was the liver or lung.
As the proportion of transplantation procedures performed with living donors increases, the preoperative waiting time is being shortened, and delays in surgery are not as important as they were in the past. We cannot, however, deny that disease progression occurs during this waiting time. Several studies have addressed the role of systemic and locoregional therapies during the waiting period. In one study, the investigators [29] found that radiofrequency ablation was safe and effective therapy for small hepatocellular carcinomas in patients with cirrhosis awaiting liver transplantation. More recent studies [30, 31] showed that aggressive multimodal therapies, including locoregional therapy and systemic chemotherapy, reduced the rate of recurrence of hepatocellular carcinoma after liver transplantation. Our result that more than 90% reduction of viable tumor volume with interventional therapy prevented tumor recurrence after liver transplantation supports the positive role of adjuvant therapies. This result is in accordance with the previous finding that a large tumor burden is a poor prognostic factor in that viable tumor volume in treated cases may be analogous to tumor burden in untreated cases. Another possible explanation is that tumors with a good response to interventional therapy have a favorable biologic nature, which contributes to a better prognosis. Two independently significant poor prognostic factors—greater than 3-cm diameter of the largest tumor and presence of intrahepatic portal venous thrombosis on CT—in our study were supportive of previous findings that tumor burden and microvascular invasion on pathologic specimens are poor prognostic factors. In a case of intrahepatic portal venous thrombosis, although we did not correlate the findings with pathologic specimens, the presence of a filling defect in an intrahepatic portion of the portal vein on contrast-enhanced CT regardless of contrast enhancement of the filling defect itself may suggest the possibility of a vascular invasion by the tumor.
All prognostic factors that turned out to be independently significant in our study seem to be supportive or repetitive of results in previous studies. However, whereas previous studies included preoperative and postoperative data, and identification of risk factors from imaging was not the focus, the data analyzed in our study were obtained exclusively with preoperative procedures, especially radiologic studies. We believe the method of data collection is the original aspect of our study in that the data are the type used in the clinical setting of planning liver transplantation in the management of hepatocellular carcinoma.
Justification of interventional therapy before liver transplantation is controversial because radiofrequency ablation and percutaneous ethanol injection therapy and transcatheter arterial chemoembolization may be responsible for tumor recurrence after liver transplantation as the result of mechanical tumor spread and possible promotion of angiogenesis, respectively. In cases of radiofrequency ablation, we adopted several strategies to minimize possible tumor seeding. These strategies include use of the fewest possible tumor punctures, avoidance of direct tumor puncture (i.e., establishment of the parenchymal electrode pathway before tumor puncture), and tract ablation during electrode withdrawal. In our population, neither univariate nor multivariate analysis yielded statistical evidence of increased risk of tumor recurrence from interventional therapy before liver transplantation.
In general, recurrence of hepatocellular carcinoma after liver transplantation is considered to result from undetected extrahepatic metastasis before surgery or the release of tumor cells during surgical manipulation [2, 7]. On the basis of this concept, we can assume that patients with recurrent hepatocellular carcinoma after liver transplantation may have a poor prognosis because the emergence of recurrent hepatocellular carcinoma means malignant cells have already spread beyond the liver and are present in other parts of the body. We ascertained as much in our study. The mortality among patients with recurrent hepatocellular carcinoma was high (56.3%), especially among patients with multiple lesions (72.7%). Although recurrence was solitary and managed with locoregional therapies, all of these patients other than those with solitary lymph node recurrence eventually had disease progression. As far as we know, there has been no well-organized analysis of the long-term results of locoregional therapy for solitary recurrence of hepatocellular carcinoma after liver transplantation. In the cases of lymph node recurrence, in which the lesions decreased in size after radiation therapy over a long follow-up period, we assumed that different types of pathogenetic mechanisms were at work.
Our study had the following limitations: First, we reviewed the cases retrospectively. Second, although the contrast-enhancement protocol for CT examinations, such as the iodine concentration of contrast medium and injection rate, was standardized, our method may not be ideal for imaging hepatocellular carcinoma. Third, our analysis of prognostic factors with only CT data, rather than pathologic data, may have yielded findings different from the actual pathologic status. Our reason for adopting this method was to comply with the purpose of the study, which was to evaluate the utility of various CT findings in the prognosis of clinical outcome among patients with recurrent tumors. Therefore, we were intentionally blinded to the results of the pathologic reports.
In conclusion, tumor recurrences after liver transplantation for unresectable hepatocellular carcinoma are not rare, and the prognosis is unfavorable. It is desirable to narrow the indications for liver transplantation for hepatocellular carcinoma to tumors with the contrast-enhanced CT findings of small size (3 cm or less) and absence of portal venous thrombosis. If the tumor is larger than 3 cm, aggressive interventional therapy is highly recommended to minimize viable tumor burden before transplantation.
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