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Original Research |
1 All authors: Gastroenterology Division of Internal Medicine, Kitasato University East Hospital, 2-1-1 Asamizodai, Sagamihara, Kanagawa 228-8520, Japan.
Received November 30, 2005;
accepted after revision February 14, 2006.
Address correspondence to T. Nakazawa
(tnakazaw{at}kitasato-u.ac.jp).
Abstract
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MATERIALS AND METHODS. Eighty-five patients with single primary hepatocellular carcinoma less than 3 cm in diameter underwent complete tumor ablation. Clinical and biochemical features, tumor characteristics, tumor location within 5 mm from intrahepatic vessels, needle biopsy before treatment, and presence of ablative margin of 5 mm or more were statistically analyzed as determinants of local tumor progression. The Kaplan-Meier method and a Cox model were used for the analyses. Patterns of local tumor progression were examined by image analysis.
RESULTS. During a median observation period of 30.3 months, 14 (16.5%) of the 85 patients had local tumor progression. The results of the log-rank test showed that the presence of vessels contiguous with the tumor (p = 0.0292) and the absence of an ablative margin of at least 5 mm (p = 0.019) significantly correlated with local tumor progression. Cox regression analysis showed that the absence of an ablative margin of at least 5 mm was an independent factor (p = 0.04). The most common pattern of local tumor progression was a single viable outgrowth from the side of the ablated area when the ablative margin was less than 5 mm. Multiple viable outgrowths were observed in one case despite the presence of an ablative margin greater than 5 mm.
CONCLUSION. An ablation zone with an ablative margin of 5 mm or greater was the most important factor for local control of hepatocellular carcinoma.
Keywords: abdominal imaging • cancer • hepatocellular carcinoma • liver disease • radiofrequency ablation
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Complete ablation of HCC is required for prevention of local recurrence and a good prognosis [6, 14]. After complete ablation, the ablation zone is completely surrounded by an avascular area with a contrast defect identifiable on dynamic contrast-enhanced CT. Despite complete ablation, however, outgrowths sometimes develop around ablated areas [15], and the presence of residual cancer cells can lead to regrowth of the tumor. Therefore, the term "local tumor progression" is more accurate than the term "local recurrence" [16]. Ablation of appropriate margins beyond the tumor is necessary to achieve complete tumor destruction, and the term "ablative margin" is proposed to describe this 0.5- to 1.0-cm-wide region [13, 16]. Ablative margin is one possible determinant of local tumor progression after complete ablation.
In this study, we examined various factors, including ablative margin, that may correlate with local progression of primary single HCC after complete radiofrequency ablation. The pattern was assessed by imaging analysis in patients with local tumor progression.
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The diagnosis of HCC was established on the basis of radiologic features
compatible with HCC on contrast-enhanced multiphase helical CT scans or
dynamic contrast-enhanced MR images (n = 45) and histologic
confirmation (n = 36). The other four patients had tumors with a
serum 
-fetoprotein level > 20 ng/dL or a level of protein induced by
vitamin K absence or antagonism II (PIVKA-II) > 40 mAU/mL. Sixty-four (75%)
of the patients had positive results for anti-hepatitis C virus, and 13 (15%)
had positive results for hepatitis B surface antigen. Fifty-nine (69%) of the
patients had a serum -fetoprotein level > 20 ng/dL or PIVKA-II level
> 40 mAU/mL. The median diameter of the HCC nodules was 20 mm (range, 10-29
mm). Tumor location was described according to Couinaud segmental anatomic
classification. Eighty-two patients had liver cirrhosis, and three had chronic
hepatitis. Clinical stage was defined according to Child-Pugh classification
and Japan Integrated Staging score
[17]. Fifty (59%) and 35 (41%)
of the patients had disease in Child-Pugh classes A and B, respectively. The
Japan Integrated Staging score was 0 in 48 patients, 1 in 36 patients, and 2
in one patient. Our study was performed in accordance with the guidelines of
our institutional review board, and written informed consent was obtained from
all patients before treatment.
Radiofrequency Thermal Ablation
Eighty-two patients were treated by percutaneous radiofrequency ablation
under real-time sonographic guidance (model 6500, Aloka Medical Systems) with
a 3.75-MHz probe. Three patients were treated under CT guidance. Fifty-five
(65%) of the patients were treated with multitined expandable electrodes, and
30 (35%) were treated with internally cooled electrodes. Conscious sedation
with a combination of pethidine hydrochloride 35 mg (Opystan, Tanabe) and
fentanyl citrate 0.1 mg (Fentanest, Sankyo) was administered IV.
Radiofrequency ablation was performed with one of three devices. Twenty-seven patients were treated with 25-cm-long, 15-gauge multitined electrodes with a 1-cm-long tip expandable by four to seven hooks to a maximum diameter of 3 cm (model 30 or 70, RITA Medical Systems). A 460-kHz radiofrequency generator (model 500PA, RITA Medical Systems) was activated, and the power needed to maintain a temperature of 90-120°C at the tip was delivered for 8 minutes. After the first ablation, the hooks were retracted, and the electrode was rotated 45°. The hooks were redeployed, and the radiofrequency generator was reactivated for an additional 8 minutes.
Twenty-eight patients were treated with hooked, 25-cm-long, 15-gauge multitined electrodes expandable by 10 hooks to a maximum dimension of 3 cm (LeVeen needle electrode, RadioTherapeutics), and radiofrequency ablation was applied with a 460-kHz radiofrequency generator (RTC 2000, Boston Scientific Japan). Initial output was set to 40 W, and the output was increased 10 W every 60 seconds until the peak power of 90 W was attained. Ablation was maintained at peak power for at least 15 minutes.
Thirty patients were treated with 25-cm-long, 17-gauge internally cooled
electrodes with an exposed 2- to 3-cm metallic tip capable of producing 200 W
of power. These electrodes were attached to a 480-kHz radiofrequency generator
(CC1, Radionics). A peristaltic pump was used to deliver chilled saline
solution in a cannula sheath of internally cooled electrodes to maintain
electrode temperature below 15°C. Radiofrequency current was emitted for
12-15 minutes per needle electrode insertion with the generator set to deliver
the maximum power in the autocontrol mode. An impedance control mode gradually
increased the power until the impedance rose to 10 
above baseline
level. To avoid a further increase in tissue temperature that would likely
result in charring, the power was reduced automatically to 10 W for 15 seconds
and returned to maximal power until the impedance increased again.
The three types of electrodes were used in the order they were introduced to our hospital. The electrodes were inserted in several sites to treat overlapping zones and to enlarge the ablation zone. The initial treatment was planned with one ablation for tumors less than 2 cm in diameter and two or more ablations for tumors with the overlapping technique for tumors 2-3 cm in diameter. When tumor ablation was complete, thermal ablation was performed along the needle track. All patients were carefully observed for treatment-related complications.
Image Analysis for HCC and Posttreatment Assessment
The following tumor characteristics were analyzed directly from CT scans
(n = 82) or MR images (n = 3): tumor size (
20 mm or
< 20 mm in diameter), location within liver, tumor type (simple round tumor
or not, subcapsular or nonsubcapsular), and presence of blood vessels (first
to third branches of the portal vein and first and second branches of the
hepatic veins) within 5 mm from the border of the HCC. A total of 120 mL of
nonionic contrast material (Omnipaque [iohexol], Daiichi Seiyaku) was
administered with an automatic power injector at a rate of 3-4.5 mL/s. Images
were obtained before and 30 and 180 seconds after initiation of injection of
IV contrast material, representing the unenhanced, hepatic arterial, and
equilibrium phases, respectively. Images were obtained in a craniocaudal
direction with 7-mm collimation and 7-mm/s table speed during a single
breath-hold helical acquisition of 25-30 seconds. The axial images were
reconstructed at intervals of 5 mm. For each patient the ablation zone was
examined on axial images in the craniocaudal direction in the same field of
view as on the hard copies obtained before and 3-5 days after treatment.
The goal of the treatment was to achieve complete ablation in the tumor
ablation zones, which were the hypoattenuating unenhanced areas visualized
during the arterial and the portal venous phases that were larger than the
tumor itself. Additional sessions were scheduled for ablation of residual
tumors when irregular peripheral enhancement was confirmed at the margin of
the ablation zone on images obtained 3-5 days after the first treatment. The
diagnosis and treatment procedures were repeated until complete ablation was
achieved during one hospital stay. The presence of an ablative margin of at
least 5 mm around the HCC (minimum measurement of ablative margin) was
examined on the final images used during the hospital stay to determine
whether ablation was complete. The ablative margin is diagrammatically shown
between the arrows in Figure
1A. All variables were assessed by one person and reviewed
retrospectively by a second person working independently. The observers
therefore were blinded with respect to patient characteristics and outcome.
Discrepancies were resolved by consensus. Subsequent diagnostic scans were
obtained 1 month after discharge. The follow-up protocol included measuring
-fetoprotein and PIVKA-II levels and acquisition of CT scans at 4-month
intervals to monitor for signs of recurrence.
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Statistical Analysis of Determinants for Local Tumor Progression
Clinical and biochemical features at the time of radiofrequency ablation,
tumor characteristics, radiofrequency ablation electrode type (multitined
expandable or internally cooled), tumor location, presence of contiguous
vessels, hepatic surface (portion of tumor located within 5 mm of the surface
of the liver), and Couinaud segment were analyzed. In addition, whether needle
biopsy was performed before ablation and whether there was a completely
ablated margin of at least 5 mm were analyzed for local tumor progression.
Data were expressed as mean ± SD. The Kaplan-Meier method was used to
estimate the interval from radiofrequency ablation treatment to local tumor
progression. The variables as determinants of local tumor progression were
analyzed with the use of the log-rank test. A Cox proportional hazards
regression model was used to analyze independent risk factors. All p
values were two-tailed. A p value < 0.05 was considered to
indicate statistical significance. Statistical analyses were performed with
the statistical package SPSS Base 11.0J (SPSS) for Windows (Microsoft).
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Table 1 shows determinants of local tumor progression. Clinical laboratory data, HCC diameter, number of treatment sessions, electrode device used, and results of tumor needle biopsy were not significantly related to tumor progression. Presence of vessels contiguous with HCC and an ablative margin of less than 5 mm were significantly related to local tumor progression. The cumulative rate of local tumor progression at 3 years was significantly higher for HCC with contiguous vessels (32%) than for HCC without contiguous vessels (5%) (p = 0.0292) (Fig. 2A). The cumulative rate of local tumor progression at 3 years was significantly lower for HCC with an ablative margin of 5 mm or more (3.5%) than for HCC with an ablative margin of less than 5 mm (28.3%) (p = 0.019) (Fig. 2B). Cox regression analysis showed that the presence of an ablative margin of less than 5 mm was a significant independent risk factor for local tumor progression (p = 0.04; relative risk = 8.475; 95% CI, 0.015-0.902). A difference between multitined expandable and internally cooled electrodes in rate of development of an ablative margin of 5 mm or more was not observed (35% vs 36%). Figure 3 classifies the lesions according to the presence or absence of contiguous vessels and whether the ablative margin was at least 5 mm or less than 5 mm. The number of HCCs with contiguous vessels and an ablative margin of at least 5 mm was significantly lower than the number of HCCs without contiguous vessels (chi-square test, p = 0.005).
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The patterns of local tumor progression are shown in Figures 4A, 4B, 4C, 4D, 5A, 5B, 5C, 5D, 5E, 6A, 6B, 6C, 6D, 6E. Outgrowths emerged from the sides of ablative margins less than 5 mm wide (Fig. 4A, 4B, 4C, 4D) and from the caudate or cranial sides of ablated regions. In one patient, a recurrence developed on the opposite side of a vessel adjacent to the ablation zone (Fig. 5A, 5B, 5C, 5D, 5E). Another patient had multiple viable recurrent lesions around the ablation zone contiguous with its border (Fig. 6A, 6B, 6C, 6D, 6E).
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Unlike the findings of previous studies [6-8], our results showed that tumor size, capsular HCCs, and location of tumor at the liver surface were not related to local tumor progression. Differences in determinants of local tumor progression may be related to the smaller size of HCCs in our study, the performance of more than two ablations with the overlapping technique for tumors 2-3 cm in diameter, and the presence of complete ablation zones with ablative margins of at least 5 mm from the tumor border. Local tumor progression occurred more than 2 years (range, 26-41.2 months) after radiofrequency ablation in four of 14 patients, and the ablative margins in those patients were less than 5 mm. Previous studies have shown that local tumor progression generally develops within 2 years after local ablation [15, 20, 21]. Thus, later local tumor progression can occur after complete ablation without a sufficient ablative margin.
Analysis by the log-rank test showed that an ablation zone including an ablative margin less than 5 mm from the tumor border and the presence of blood vessels contiguous with tumors were significantly related to local tumor progression. Multivariate analysis showed that presence of an ablative margin of at least 5 mm was a significant independent factor for local tumor progression. An adequate ablative margin is required because most recurrent lesions emerge from ablation zones within 5 mm from the tumor border, the area most likely to contain viable tumor cells. We found that outgrowth emerged from the side of an incompletely ablated margin, including the caudal and cranial ends of the ablated areas, possibly where the ablative margin was underestimated on single-section helical CT scans obtained after radiofrequency ablation. Local tumor progression also occurs beyond vessels adjacent to an ablation zone in cases of HCC with contiguous vessels (Fig. 5A, 5B, 5C, 5D, 5E). To inhibit local tumor progression, both stricter evaluation of ablation zones with imaging techniques such as MDCT and the use of radiofrequency techniques to enlarge ablation zones are necessary.
Because techniques such as overlapping insertions of electrodes sometimes produce small ablation zones relative to the number of ablations [13], other tumor ablation strategies, such as saline or ethanol injections before radiofrequency ablation and the use of devices such as cooled-tip triple-cluster needles, are effective for developing larger areas of ablation with adequate ablative margins [22-25]. Okusaka et al. [26] reported that small single HCCs (3 cm or less in diameter) with no satellite lesions on preoperative images had microscopic satellite lesions 0.5-1.0 cm from the main tumor. These findings suggest the need for an ablative margin of 0.5-1.0 cm around tumors treated with ablation. Because excessively large ablation zones adjacent to blood vessels can cause intravascular thrombosis [27], radiofrequency ablation procedures must be carefully monitored.
Our findings suggest that it is difficult to develop an ablative margin of at least 5 mm in the management of HCC with contiguous vessels (Fig. 3). Blood flow reduces the thermal effects of radiofrequency ablation, a phenomenon that increases the likelihood of the presence of residual viable tumor cells [24, 28, 29]. To avoid the heat-sink effects of large vessels, radiofrequency ablation with balloon occlusion of the hepatic vessels, a technique that achieves more extensive ablation than standard radiofrequency ablation, can be used to manage HCC with contiguous vessels [28, 30]. Thus, an ablative margin of 5 mm or more should be required in the management of HCC, especially of lesions with contiguous blood vessels.
In cases of HCC without contiguous vessels, local tumor progression was not different in the ablation zones, as shown in Figure 3. The absence of contiguous blood vessels in HCC was significantly associated with location of the tumor near the surface of the liver (n = 24) compared with the presence of contiguous vessels (n = 13) (chisquare test, p = 0.012). The findings suggest that because there is less influence of blood flow around the tumor, the absence of contiguous vessels in HCC allows ablation of necrotic tissue that is closer than can be achieved when contiguous vessels are present. In addition, radiofrequency ablation of tumors at the hepatic surface can leave an area of scar contraction on the liver. These factors might have contributed to the results related to width of ablative margin and local tumor progression in the cases of HCC without contiguous vessels.
The present study had several limitations. It was performed as a retrospective singlecenter study, and three models of devices were used for radiofrequency ablation under sonographic guidance, possibly leading to bias. To reduce the effects of the other factors, we focused on patients who had primary single small HCC that was completely ablated. These results must be confirmed in larger prospective studies.
In conclusion, the presence of blood vessels contiguous to HCC is related to local tumor progression after radiofrequency ablation. A margin of at least 5 mm around HCC should be completely ablated along with the tumor. This factor is most important for local control. Because single or multiple lesions can develop around ablation zones despite the presence of an ablative margin of more than 5 mm, patients should be closely observed, and follow-up examinations should be done at regular intervals. Further studies of the mechanism of local tumor progression after radiofrequency ablation are essential for defining the factors involved.
Acknowledgments
We thank Naomi Kakutani for assistance preparing the figures. We also thank
Robert E. Brandt for help editing the manuscript.
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