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Published online before print March 29, 2005, 10.1148/radiol.2352040425
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(Radiology 2005;235:478-486.)
© RSNA, 2005

Experimental Studies

Porcine Liver: Morphologic Characteristics and Cell Viability at Experimental Radiofrequency Ablation with Internally Cooled Electrodes1

Kelvin K. Ng, MBBS, FRCS(Edin)(Gen Surg), Chi Ming Lam, MBBS, MS, FRCS(Edin), Ronnie T. Poon, MBBS, MS, FRCS(Edin), FACS, Tony W. Shek, MBBS, FRCPath, Wan Ching Yu, MBBS, Jensen Y. To, Yim Hung Wo, VMD, Cecilia P. Lau, BMedLSc, MPhil, Terence C. Tang, MSc, David W. Ho, BMedLSc, MPhil and Sheung Tat Fan, MS, MD, PhD, FRCS(Glasg & Edin), FACS

1 From the Departments of Surgery (K.K.N., C.M.L., R.T.P., W.C.Y., J.Y.T., Y.H.W., C.P.L., T.C.T., D.W.H., S.T.F.) and Pathology (T.W.S.) and Centre for the Study of Liver Disease, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Rd, Hong Kong, China. Received March 3, 2004; revision requested May 14; revision received June 4; accepted July 8. Supported by Distinguished Research Achievement Award and Sun C. Y. Research Foundation for Hepatobiliary and Pancreatic Surgery of the University of Hong Kong. Address correspondence to K.K.N. (e-mail: kcng66@yahoo.com).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate morphologic characteristics and cell viability of radiofrequency ablation zones in porcine liver.

MATERIALS AND METHODS: Approval of the study protocol was obtained from the Ethics Committee on Use of Live Animals for Teaching and Research at University of Hong Kong. Internally cooled electrodes were used to produce 120 ablated zones ex vivo and 60 ablated zones in vivo with single electrodes (1-, 2-, and 3-cm exposed lengths) or clustered electrodes (1.0-, 2.0-, and 2.5-cm exposed lengths) at 4, 8, 12, and 16 minutes of ablation (ex vivo) and 8 and 12 minutes of ablation (in vivo). Morphologic measurements of each ablated zone were performed. Cell viability in each ablated zone was assessed qualitatively with histochemical staining and quantitatively with measurement of intracellular adenosine 5'-triphosphate (ATP) concentration.

RESULTS: Exposed length of electrode (coefficient = 0.79, standard error = 0.04, P < .001), duration of ablation (coefficient = 0.14, standard error = 0.01, P < .001), and clustered electrode design (coefficient = 1.21, standard error = 0.05, P < .001) were independent factors that affected minimal transverse diameter and volume of ablated zone in ex vivo study. Similar morphologic characteristics existed among ablated zones in in vivo study. Mean distance of ablation beyond the electrode tip remained constant (ex vivo, 1.0 cm ± 0.08 [standard deviation]; in vivo, 0.5 cm ± 0.05) regardless of different ablation conditions. Histochemical staining revealed no viable hepatocytes from center to margins of white zone in each ablated area. Mean intracellular ATP concentration in margins of white zone (9.5 x 10–12 mol/µg DNA ± 1.43) was lower than that in red zone (4088 x 10–12 mol/µg DNA ± 65.97, P < .001) and in adjacent normal liver (4528 x 10–12 mol/µg DNA ± 52.74, P < .001).

CONCLUSION: Distance of ablation beyond the tip of the electrode remained constant (ex vivo, 1.0 cm; in vivo, 0.5 cm) with different conditions of ablation. Complete and uniform cellular destruction was achieved in the white zone of ablated area.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Localized thermal ablation therapy has been widely adopted in the management of unresectable malignant liver tumors (1–3). Its main advantage is the ability to cause in situ tumor destruction while the maximal volume of normal liver parenchyma is preserved. This is particularly important in patients with limited liver functional reserve, such as those with underlying liver cirrhosis. Radiofrequency (RF) ablation is one of the recently developed thermal ablation therapies (3). At RF ablation, high-frequency alternating current (350–500 kHz) is used to generate frictional heat energy with ionic vibration within the tumor cells. At temperatures of greater than 60°C, there is denaturation of intracellular protein and lipid bilayers, which leads to irreversible cell death (4). Even at lower temperatures (50°–55°C), irreversible cell damage can be achieved with the process of ablation for 4–6 minutes (5). Researchers in clinical studies have demonstrated the safety of RF ablation in the management of unresectable primary and secondary malignant liver tumors, with low morbidity (0%–12%) and mortality (0%–3%) rates (6–12). The long-term results of RF ablation for hepatocellular carcinoma are also encouraging, with a reported 5-year survival rate of 33%–40% (13,14).

Despite its safety and effectiveness, one main limitation of RF ablation is the high tumor recurrence rate (range, 18%–60%) in tissue adjacent to previously ablated areas (10,11,14–17). This is largely related to the incomplete ablation of tumor cells during the treatment procedure. The possible underlying reasons include: (a) a poor understanding of the geometry of the zone of RF ablation in relation to the RF electrode, (b) the incomplete tumor ablation at margins of ablated tissue, and (c) the presence of residual viable cells within the ablated zone. In a recent review about the results of experimental hepatic RF ablation, researchers showed that there were insufficient data in regard to the size and geometry of the ablated zone for many types of commercially available RF electrodes (18).

The RF system with an internally cooled RF electrode (Cool-tip; Radionics, Burlington, Mass), which is one of the Food and Drug Administration–approved RF systems, has been widely used for patients with primary and secondary liver tumors (7,11,12,15). To our knowledge, there has been no detailed study of this system to document the exact morphologic features of the ablated zone in relation to the position of the RF electrode. Besides, researchers in clinical and experimental studies have revealed histologic evidence of coagulative necrosis within the ablated zones with RF ablation (19,20). Yet, the completeness of ablation has only been assessed with histochemical staining in a few studies (21,22). Thus, the purpose of our study was to evaluate the morphologic characteristics of zones of RF ablation produced by internally cooled electrodes and to evaluate the cell viability qualitatively and quantitatively within these ablated zones in a porcine liver model.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Ex vivo studies in porcine liver specimens and in vivo studies in domestic pigs were performed to investigate the characteristics of zones of RF ablation by using internally cooled electrodes. Approval of the study protocol was obtained from the Ethics Committee on the Use of Live Animals for Teaching and Research at the University of Hong Kong, Hong Kong, China.

RF Ablation System
The RF ablation system with an internally cooled RF electrode was used in the present study. This system consisted of an RF generator to produce RF current of 480 kHz at a maximal power of 200 W, an RF electrode with either a single or clustered probe, a water-pumping machine, and return grounding pads. The single-probe electrode was 17 gauge and contained internal dual channels through which chilled water was pumped by a peristaltic pump. The resultant cooling effect around the electrode tip could reduce charring of the surrounding tissue that might decrease tissue conductivity and block the RF current. Experiments have shown that this internally cooled electrode design could help to effectively increase the size of the ablated zones (23,24).

The cluster-probe electrode comprised three single electrodes placed in close proximity to each other (0.5 cm apart). A plastic block was available in the system to keep the three single electrodes 0.5 cm apart during the process of ablation. The synergistic effect among the three single electrodes could further help to increase the volume of ablated tissue. During the procedure, the RF system would automatically monitor the tissue impedance between the RF electrode and the grounding pads. Whenever there was an increase of 20{Omega} greater than the baseline impedance level, the generator would temporarily turn off the RF current for 15 seconds. In an experimental study, researchers have shown that this pulsed RF current could optimize the preferential tissue cooling around the RF electrode to produce a large volume of ablation (25).

Ex Vivo Study: Procedure and Evaluation
Twenty entire porcine liver specimens were obtained from a slaughterhouse. The liver was stored in an incubator at 37.5°C for 15 minutes before use. During the experiment, the porcine liver was placed on a metal plate connected to the grounding pads of the internally cooled RF system. The zones of RF ablation were produced by using different exposed lengths of the RF electrodes (1, 2, and 3 cm for single electrodes; 1.0, 2.0, and 2.5 cm for clustered electrodes) and durations of ablation (4, 8, 12, and 16 minutes). Five zones, with each combination of conditions, of ablation were produced, and a total of 120 ablated zones were studied by one investigator (K.K.N.).

Single electrodes with 2 and 3 cm of exposed length and clustered electrodes with 2.5 cm of exposed length were used for all phases of the experiments. For ablation with 1 cm of exposed length in single electrodes and that with 1.0 or 2.0 cm of exposed length in clustered electrodes, only portions of the exposed lengths of the electrode were inserted into the liver parenchyma in each combination of the conditions of ablation. Each ablated zone was then dissected from the porcine liver. The morphologic characteristics of each ablated zone were measured with respect to the minimal transverse diameter, minimal longitudinal diameter, and distance of ablation beyond the electrode tip (Fig 1). In addition, the volume of the ablated zone was measured by means of the fluid displacement technique: The tissue of the whole ablated zone was immersed into a cylinder containing 100 mL water, and the volume of this tissue was measured with measurement of the displaced water.



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  		Figure 1. Schematic shows morphologic measurements of each ablated zone (A) in ex vivo and in vivo studies. D1 = minimal transverse diameter, D2 = minimal longitudinal diameter, D3 = distance of ablation beyond the electrode tip.

 
In Vivo Study: Procedure and Evaluation
RF ablation was performed in 10 domestic pigs that weighed 35–40 kg. In these pigs, food intake was withheld (for fasting) for 8 hours before the experiment. During the experiment, intramuscular injections of 50 mg/kg ketamine hydrochloride and 0.12 mg of atropine sulfate were administered to each pig for induction of anesthesia. Then each pig was anesthetized with an intravenous injection of 0.5 mg/kg midazolam hydrochloride and 4 mg of pancuronium bromide. Endotracheal intubation was performed, and general anesthesia was maintained with inhalation of 1% isoflurane with a mixture of oxygen and nitric oxide at a ratio of 1:3. Cardiac and respiratory parameters were monitored throughout the experiment. All the anesthetic procedures were performed by one researcher (J.Y.T.). Four grounding pads were placed on both thighs of the pigs. Povidone-iodine solution (10%) was applied over the abdomen, and laparotomy was performed through a midline incision.

The falciform ligament to the liver was divided. With normal hepatic blood flow, zones of RF ablation were produced by using internally cooled electrodes in the same way as the zones were produced for the ex vivo study, with different exposed lengths of the electrodes (1, 2, and 3 cm for single electrodes; 1.0, 2.0, and 2.5 cm for clustered electrodes) and durations of ablation (8 and 12 minutes). A total of 60 zones of RF ablation were examined. We produced one zone of RF ablation in each segment of the porcine liver with different conditions of ablation (26). There was no alteration of hepatic blood flow during the process of ablation. All the surgical procedures, including RF ablation, were performed by two researchers (K.K.N. and Y.H.W). The pigs were then sacrificed after all RF ablation procedures with an intravenous injection of 100 mg/kg pentobarbital sodium.

The same morphologic measurements of each ablated zone as those that were performed in the ex vivo study were performed by one investigator (K.K.N.). Three distinct zones were identified in each ablated area, namely a center, a white zone, and a peripheral red zone (Fig 2). The margins of the white zone were considered as the margins of the ablated area. In addition, the cell viability within each ablated zone was determined qualitatively and quantitatively. For qualitative measurements, paraffin and frozen sections of each ablated zone were treated with hematoxylin-eosin and histochemical staining, respectively. All histologic slides were reviewed by a qualified pathologist (T.W.S.), who had more than 10 years of experience in liver histopathologic analysis. The nicotinamide adenine dinucleotide technique was used in histochemical staining (C.P.L. and T.C.T.) to detect cellular mitochondrial viability (27).



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  		Figure 2. Specimen with ellipsoidal zone of RF ablation (38 x 22 mm), which was produced with single RF electrode with 3-cm exposed length at 4 minutes of ablation in in vivo study. C = center containing the shaft of the RF electrode, R = red zone, W = white zone.

 
Reduced nicotinamide adenine dinucleotide solution (Sigma Diagnostics, St Louis, Mo) at a concentration of 0.1 mg/mL was mixed with the indicator nitroblue tetrazolium at a concentration of 1.0 mg/mL. Sections (5 µm in thickness) of samples from each ablated zone (center, margins of white zone, red zone, and adjacent nonablated liver tissue) were placed in a cryostat, incubated in the solution for 30 minutes at room temperature, and then examined with the microscope. For quantitative measurements, the intracellular adenosine 5'-triphosphate (ATP) concentration of hepatocytes within each ablated zone was determined by using bioluminescence analysis (Bioluminescence Assay Kit HSII; Roche Diagnostics, Mannheim, Germany) of ATP (28,29).

We harvested representative tissue samples (5 mm in diameter) from the center and the margins of the white zone and of the red zone of each ablated area (five representative samples from each region). The margins of the white zone were considered as the margins of each ablated area. Five control samples (the same size as samples from the ablated zone) were removed from the adjacent nonablated liver at a point at least 10 cm from the ablated area. Each tissue sample was mixed with the lytic reagent provided with the kit and was sonicated for 30 seconds. The sample was then centrifuged at 3000 rpm for 5 minutes, and the supernatant that contained intracellular material was aspirated for further study. An ATP-dependent light-emitting luciferase reagent (50 µL) was added to each sample, and the ATP content (10–12 mol/mL) was measured (Luminometer, model TD-20/20; Turner Designs, Sunnyvale, Calif). To standardize the unit of ATP concentration of each sample, the corresponding DNA content (expressed in micrograms per milliliter) of the supernatant was calculated with measurement of the absorbance at a wavelength of 260 nm, and the unit of ATP concentration was expressed as 10–12 mol/µg DNA. This quantitative intracellular ATP measurement was performed by two researchers (D.W.H. and W.C.Y.).

Statistical Analysis
The mean coagulation diameter produced by the internally cooled electrode in ex vivo liver specimens and in in vivo porcine liver has been reported to be 3.5 cm ± 0.1 (standard deviation) and 3.3 cm ± 0.2, respectively (30). If one assumes that the coagulation diameter would have at least a 30% change in different conditions of ablation, one may calculate that three trials of ablation would be needed for each combination of ablation conditions to demonstrate a significant change in coagulation diameter, with an 80% power at the .05 level of significance by using a two-sided unpaired t test. Hence, five trials of ablation were performed for each ablation condition in the present ex vivo and in vivo experiments. Statistical software (SPSS, version 10; SPSS, Chicago, Ill) and a statistical analysis system (SAS, version 8.2; SAS Institute, Cary, NC) were used to analyze the results.

The unpaired t test was used to compare continuous variables between groups. Individual factors (the exposed length of the electrode, the duration of ablation, and the electrode design) that affected each morphologic measurement (minimal transverse diameter, minimal longitudinal diameter, distance of ablation beyond the electrode tip, and volume) of the ablated zones were subjected to univariate analysis with a linear regression model. A multilevel model was used to examine the effects of independent factors for each morphologic measurement (31). This approach was used to account for the potential association among the ablated zones from the same liver. Normal probability plots and residual plots were used to assess the validity of the model. Analysis of the volume of the ablated zone was logarithmically transformed because departures from model assumption were observed in both the normal probability plots and the residual plots. A P value of less than .05 was considered to indicate a statistically significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Ex Vivo Study
All zones of RF ablation were ellipsoidal (Fig 2). For the single RF electrode, the minimal transverse diameter correlated positively with the exposed length of the RF electrode (coefficient = 0.61, standard error = 0.11, P < .001) and the duration of ablation (coefficient = 0.14, standard error = 0.01, P < .001) with univariate analysis (Fig 3a). A significant correlation also existed between the minimal longitudinal diameter and the exposed length of the RF electrode (coefficient = 0.98, standard error = 0.02, P < .001) (Fig 3b). There was no relationship, however, between the minimal longitudinal diameter and the duration of ablation (P = .465). When we measured the distance of ablation beyond the electrode tip, we found that it remained constant (mean = 1.0 cm ± 0.09) despite the increased exposed length of the RF electrode (P = .136) and increased duration of ablation (P = .981) (Fig 3c). There was a positive correlation between the volume of the ablated zone and the exposed length of the RF electrode (coefficient = 10.81, standard error = 1.22, P < .001) and duration of ablation (coefficient = 1.56, standard error = 0.27, P < .001) (Fig 3d).



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  		Figure 3a. Graphs show measurements in ex vivo study with single RF electrode and 1-cm (dotted line), 2-cm (dashed line), and 3-cm (solid line) exposed lengths at 4, 8, 12, and 16 minutes of ablation. (a) Minimal transverse diameter. (b) Minimal longitudinal diameter. (c) Distance of ablation beyond the electrode tip. (d) Volume of ablated zones.

 


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  		Figure 3b. Graphs show measurements in ex vivo study with single RF electrode and 1-cm (dotted line), 2-cm (dashed line), and 3-cm (solid line) exposed lengths at 4, 8, 12, and 16 minutes of ablation. (a) Minimal transverse diameter. (b) Minimal longitudinal diameter. (c) Distance of ablation beyond the electrode tip. (d) Volume of ablated zones.

 


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  		Figure 3c. Graphs show measurements in ex vivo study with single RF electrode and 1-cm (dotted line), 2-cm (dashed line), and 3-cm (solid line) exposed lengths at 4, 8, 12, and 16 minutes of ablation. (a) Minimal transverse diameter. (b) Minimal longitudinal diameter. (c) Distance of ablation beyond the electrode tip. (d) Volume of ablated zones.

 


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  		Figure 3d. Graphs show measurements in ex vivo study with single RF electrode and 1-cm (dotted line), 2-cm (dashed line), and 3-cm (solid line) exposed lengths at 4, 8, 12, and 16 minutes of ablation. (a) Minimal transverse diameter. (b) Minimal longitudinal diameter. (c) Distance of ablation beyond the electrode tip. (d) Volume of ablated zones.

 
Similar morphologic characteristics were obtained for the clustered RF electrodes, which produced larger lesions (increased minimal transverse diameter and volume of ablated zone) than those created with single electrodes for any conditions of ablation (Fig 4a, 4d). Nevertheless, the corresponding minimal longitudinal diameter was not correlated with the duration of ablation (P = .726) (Fig 4b), and the distance of ablation beyond the electrode tip remained constant (mean = 1.0 cm ± 0.06) with different conditions of ablation (Fig 4c). A multilevel model showed that the exposed length of the RF electrode (coefficient = 0.79, standard error = 0.04, P < .001), the duration of ablation (coefficient = 0.14, standard error = 0.01, P < .001), and the type of RF electrode (coefficient = 1.21, standard error = 0.05, P < .001) were the independent factors that affected the minimal transverse diameter of ablated zones. The same factors (exposed length of the electrode, duration of ablation, and type of RF electrode) also influenced the volume of ablated zones independently. The exposed length of the RF electrode (coefficient = 1.04, standard error = 0.01, P < .001) was the only independent factor that affected the minimal longitudinal diameter of ablated zones (Table 1). None of the factors (exposed length of the electrode, duration of ablation, and type of RF electrode) was found to influence the distance of ablation beyond the electrode tip (mean = 1.0 cm ± 0.08).



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  		Figure 4a. Graphs show measurements in ex vivo study with clustered RF electrode and 1.0-cm (dotted line), 2.0-cm (dashed line), and 2.5-cm (solid line) exposed lengths at 4, 8, 12, and 16 minutes of ablation. (a) Minimal transverse diameter. (b) Minimal longitudinal diameter. (c) Distance of ablation beyond the electrode tip. (d) Volume of ablated zones.

 


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  		Figure 4b. Graphs show measurements in ex vivo study with clustered RF electrode and 1.0-cm (dotted line), 2.0-cm (dashed line), and 2.5-cm (solid line) exposed lengths at 4, 8, 12, and 16 minutes of ablation. (a) Minimal transverse diameter. (b) Minimal longitudinal diameter. (c) Distance of ablation beyond the electrode tip. (d) Volume of ablated zones.

 


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  		Figure 4c. Graphs show measurements in ex vivo study with clustered RF electrode and 1.0-cm (dotted line), 2.0-cm (dashed line), and 2.5-cm (solid line) exposed lengths at 4, 8, 12, and 16 minutes of ablation. (a) Minimal transverse diameter. (b) Minimal longitudinal diameter. (c) Distance of ablation beyond the electrode tip. (d) Volume of ablated zones.

 


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  		Figure 4d. Graphs show measurements in ex vivo study with clustered RF electrode and 1.0-cm (dotted line), 2.0-cm (dashed line), and 2.5-cm (solid line) exposed lengths at 4, 8, 12, and 16 minutes of ablation. (a) Minimal transverse diameter. (b) Minimal longitudinal diameter. (c) Distance of ablation beyond the electrode tip. (d) Volume of ablated zones.

 

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  		TABLE 1. Factors That Affected Morphologic Features: Multilevel Model in ex Vivo Study

 
In Vivo Study
All morphologic measurements (minimal transverse diameter, minimal longitudinal diameter, distance of ablation beyond the electrode tip, and volume) of the ablated zones in the in vivo study were significantly smaller than those in the ex vivo study, with the same conditions of ablation (Tables 2, 3). Nevertheless, morphologic characteristics among the ablated zones in the in vivo study were similar to those in the ex vivo study. In particular, we found that the distance of ablation beyond the electrode tip remained constant (mean = 0.5 cm ± 0.05), and it was significantly shorter than that in the ex vivo study (P < .001), regardless of the increased duration of ablation (P = .595) and the use of different RF electrodes (P = .744) with various exposed lengths (P = .353) (Fig 5).


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  		TABLE 2. Comparison of Morphologic Measurements of All Zones of RF Ablation in ex Vivo and in Vivo Studies with Single RF Electrode

 

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  		TABLE 3. Comparison of Morphologic Measurements of All Zones of RF Ablation in ex Vivo and in Vivo Studies with Clustered RF Electrode

 


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  		Figure 5. Graph shows distance of ablation beyond the electrode tip in in vivo study with single RF electrode (dotted line) with 1-, 2-, and 3-cm exposed lengths and clustered RF electrode (dashed line) with 1.0-, 2.0-, and 2.5-cm exposed lengths at 8 and 12 minutes of ablation.

 
At histologic examination with hematoxylin-eosin staining, there were physical damage to the hepatic architecture and scattered thrombosed small vessels (<3 mm) in the white zone (Fig 6). In addition, there was intense congestion of sinusoids, with erythrocytes in the peripheral red zone (Fig 7).



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  		Figure 6. Specimen shows physical damage to liver lobule within zone of RF ablation that resulted from formation of microbubbles during the process of ablation (D) and scattered thrombosed small vessels (V). (Hematoxylin-eosin stain; original magnification, x50.)

 


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  		Figure 7. Histologic specimen shows congestion of sinusoids with erythrocytes in the red zone (R) of the zone of ablation, compared with the white zone (W), which lacks these histologic features. (Hematoxylin-eosin stain; original magnification, x100.)

 
There was complete cellular destruction in the ablated zones from the center to the ablated margins of the white zone, as determined with histochemical staining and intracellular ATP measurement. Histochemical staining of representative cross-sectional tissue samples showed that the liver parenchyma did not accept staining from the center to the ablated margins of the white zone, which indicated nonviability of the liver tissue. On the other hand, the red zone accepted staining, and a clear-cut transition zone existed between the viable and nonviable tissue at the ablated margins of the white zone and red zone, respectively (Fig 8). The ablated margins of nonviable tissue, as determined at histochemical staining, matched those observed at gross examination of each ablated zone. In regard to the quantitative measurements of cell viability within the ablated zones, the mean intracellular ATP concentration in the center (mean = 8.75 x 10–12 mol/µg DNA ± 1.33) was comparable with that at the margin of the white zone (mean = 9.5 x 10–12 mol/µg DNA ± 1.43) (P = .44) but was significantly lower than that in the red zone (mean = 4088 x 10–12 mol/µg DNA ± 65.97) (P < .001) and in the adjacent normal liver tissue (mean = 4528 x 10–12 mol/µg DNA ± 52.74) (P < .001). There was no significant difference in ATP concentration between the red zone and the adjacent normal liver tissue (P = .37).



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  		Figure 8. Specimen shows clear-cut demarcation (dashed line) between viable (V) and nonviable tissue (N) at the margins of the white zone and red zone in each ablated area. (Histochemical stain; original magnification, x100.)

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
REFERENCES
 
To date, more than 3000 patients with malignant liver tumors have been treated with RF ablation (1,3,8–10,32). Although data about the long-term survival of patients who underwent RF ablation are limited, local tumor recurrence in tissue adjacent to the ablated site has been frequently reported (10,11,14–17). The associated risk factors for local tumor recurrence after RF ablation include large tumor size (>4 cm in diameter), multiple tumor nodules (more than two), major vascular invasion by tumor, and percutaneous approach for RF ablation (17,33–36).

To achieve the same local tumor control with RF ablation as is achieved with hepatic resection, which is the curative treatment of choice for malignant liver tumors, we need to verify the exact morphologic characteristics of the zone of RF ablation in relation to the position of the RF electrode during each process of ablation so that the targeted tumor can be completely ablated with a sufficient ablated margin. There were only a few scientific reports in which this issue was addressed during the early development of RF ablation treatment for liver tumors.

Goldberg et al (37) studied the effect of electrode size, electrode tip temperature, and treatment duration on the extent of coagulation necrosis with conventional monopolar RF electrodes in ex vivo liver. In that study, the increased length of the electrode tip was associated with a linear increase in the longitudinal diameter of coagulation area, whereas the treatment duration was shown to affect the transverse diameter of coagulation but not the longitudinal diameter. Similar results were obtained by the same group of authors with internally cooled electrodes, except that the RF energy deposited into the tissue and the resultant coagulation necrosis were significantly greater than those achieved with the conventional electrode (30). The extent of coagulation necrosis induced with RF ablation in relation to the position of the RF electrode, however, was not mentioned clearly, particularly the distance of ablation beyond the electrode tip. This information was important for placement of the RF electrode in an optimal position to ensure complete tumor ablation. A recent review by Mulier et al (18) revealed that there were incomplete experimental data on the size and geometry of hepatic RF ablation zones in 17 of 28 commercially available RF electrodes.

In our study, we delineated the actual morphology of the zone of RF ablation with respect to the position of the internally cooled RF electrode. In our study, the morphologic measurements of the ablated zones were comparable with those obtained by other researchers (Table 4), except that the ex vivo and in vivo ablated zones produced by the clustered electrode with 2.5-cm exposed length were larger than those produced by the other researchers (30,38,39). With the different conditions of ablation, all ablated zones were ellipsoidal, with high predictability and reproducibility. The fact that morphologic measurements in the in vivo study were significantly smaller than those in the ex vivo study could be explained by the "heat-sink" effect of hepatic blood flow on the lesion treated with RF ablation, as suggested by other researchers (40–43).


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  		TABLE 4. Morphologic Measurements of Zones of RF Ablation with Clustered RF Electrodes in Experimental and Clinical Studies

 
The findings of our experiments coincided with the results of the work of Goldberg et al (30) in that the maximal transverse diameter and volume of ablated zones correlated positively with the increased exposed length of the RF electrode, the duration of ablation, and the use of the clustered electrode. In addition, we observed an important finding in regard to the morphologic characteristics of the zone of RF ablation that was not mentioned in the literature. In both ex vivo and in vivo experiments, the deep margin of each ablated zone extended beyond the tip of the electrode at a constant distance (ex vivo, 1.0 cm; in vivo, 0.5 cm), irrespective of the different conditions of ablation with either a single or a clustered internally cooled electrode.

The other concern for the possible local failure of RF ablation is related to the cell viability within the zone of RF ablation, especially the cell viability at the ablated margins. At a temperature of 60°–100°C during RF ablation treatment, there is instant protein coagulation, which irreversibly damages the mitochrondrial enzymes, as well as the nucleic acid–histone protein (44,45). Cells within the ablated zone will undergo coagulative necrosis, and thus irreversible cell death occurs shortly after the process of ablation. At present, only qualitative measures have been adopted to denote cellular destruction during RF ablation. Kruskal et al (20) described the cellular alteration during RF ablation of liver tissue in mice. Five discrete zones were shown to extend outward from the RF electrode, namely, tissue coagulation, cellular edema, sinusoidal stasis, parenchymal shunting, and normal liver tissue. The actual cellular necrosis was limited to the zone of tissue coagulation (white zone) at histologic examination, as shown in our study.

Scudamore et al (19) employed the histochemical staining technique by using reduced nicotinamide adenine dinucleotide solution to detect the intracellular oxidative enzyme of hepatocytes within the zone of RF ablation. At microscopic examination, all ablated zones were clearly defined with this staining technique, which delineated the nonviable cells in the ablated zone. Besides, there are other tests for assessment of cell viability, with high accuracy. 2,3,5-Triphenyltetrazolium chloride is a reagent for oxidative intracellular enzymes, and the immersion method with this chemical is a reliable means to detect ischemic injury of cells (46). The lactate dehydrogenase leakage test is another sensitive method for assessment of cell viability of liver slices in vitro (47).

We adopted both qualitative and quantitative measures to investigate the viability of cells within the zones of RF ablation. For qualitative measures with the histochemical staining technique, there was a clear demarcation between nonviable hepatocytes in the ablated margins of the white zone and viable hepatocytes at the red zone of each ablated area. Measurement of the intracellular ATP concentration has been used to determine the cell viability of in vitro liver slices in experimental studies, with high sensitivity and specificity (29,48). We applied this method to measure the cell viability at the center and margins of each ablated zone in a quantitative manner. Our results in the in vivo study showed that the nonviable hepatocytes extended from the center to the ablated margins of the white zone in each area treated with RF ablation. Although some authors considered the erythrocyte-congested outer zone of the area treated with RF ablation as the ablated margin (40,49), we considered the margins of the white zone, which were used for the geometric measurements of all ablated zones, as such. This was because viable hepatocytes were detected in the outer red zone with the histochemical staining technique and the intracellular ATP measurement. Our study results suggested that complete cellular ablation could be achieved within the whole zone of RF ablation to the margins of the white zone.

The morphologic characteristics of the zone of RF ablation in our experiments were limited to the ablated area near the liver surface, where the diameter of the blood vessels was small to medium (<3 mm). The RF current may cause thrombosis of these vessels, and the final morphologic characteristic of the zone of RF ablation remained ellipsoidal. Large intrahepatic vessels, however, may have a significant negative heat-sink effect against the RF current, which may deform the final morphologic characteristic of the lesion treated with RF ablation. In a separate experiment, we demonstrated that, with intact intrahepatic blood flow, the RF-induced coagulative necrosis could extend around the major portal vein branch, which did not suffer from thermal injury. Hepatocytes within the white zone of ablation, adjacent to the large blood vessel, remained nonviable, as evidenced with qualitative and quantitative measurements (50).

The main limitation of this study was the use of normal liver as the substrate for the RF ablation procedure. Cirrhotic liver, as well as liver tumor, might have different conductivity for the RF current, and the final morphologic characteristics of the ablated zone might vary. Further studies with a cirrhotic liver model are needed to verify this issue. Moreover, only internally cooled electrodes with constant exposed lengths (2 and 3 cm for single electrodes; 2.5 cm for clustered electrodes) were used throughout the experiments. It would have been desirable to have measurements with the RF electrodes and all the exposed lengths available for this study. The specific internally cooled electrodes (single electrodes with 1-cm exposed length; clustered electrodes with 1.0- and 2.0-cm exposed lengths), however, were not commercially available. Another major limitation of our study was that we strictly focused on the use of internally cooled electrodes. Additional studies with similar approaches and other types of electrodes, such as multitined expandable electrodes, are needed.

In conclusion, the distance of ablation beyond the electrode tip with the RF ablation system with the internally cooled RF electrode remained constant (ex vivo, 1.0 cm; in vivo, 0.5 cm) with different conditions of ablation in our study in normal liver. This finding can provide guidance to optimize the positioning of the internally cooled electrode in clinical practice to achieve an adequately deep ablated margin, although studies with a tumor model are needed. Findings of this study also demonstrate that complete cellular destruction can be achieved within the whole zone of RF ablation to the ablated margins of the white zone.

Practical application: The finding of constant ablation distance beyond the electrode tip has enlightened us about the optimal position of the internally cooled RF electrode during RF ablation treatment to achieve an adequately deep ablated margin. The formation of microbubbles from the vaporization of intracellular water during the process of ablation could cause physical damage to the hepatic parenchyma. In addition, it would obscure the view at ultrasonography, and good monitoring of all margins of the ablated zone may be difficult. Therefore, it is necessary to predict the extent of the deep ablated margins and to plan the position of the RF electrode to ensure complete ablation of the targeted lesion in clinical practice. Because a tumor-free margin of 1 cm has been generally accepted for surgical resection for primary liver cancer (51,52), the RF electrode should be advanced through the tumor for at least 0.5 cm beyond its deep margin if one wishes to achieve a 1-cm tumor-free ablation margin.


   ACKNOWLEDGMENTS
 
The authors thank Louis Chow Wing Cheong, MBBS, MS, and Wing Tjing Yung Loo, BM, MSc, for their advice and assistance in the experiments.


   FOOTNOTES
 
Abbreviations: ATP = adenosine 5'-triphosphate, RF = radiofrequency

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, K.K.N.; study concepts, K.K.N.; study design, K.K.N., C.M.L., R.T.P.; literature research, K.K.N.; experimental studies, K.K.N., T.W.S., W.C.Y., Y.H.W., J.Y.T., C.P.L., T.C.T., D.W.H.; data acquisition and analysis/interpretation, K.K.N.; statistical analysis, K.K.N.; manuscript preparation and definition of intellectual content, K.K.N.; manuscript editing and revision/review, C.M.L., R.T.P., S.T.F.; manuscript final version approval, S.T.F.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
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