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Original Research |
1 Department of Radiology, Kangwon National University College of Medicine,
Kangwon-do, South Korea.
2 Department of Radiology and Center for Imaging Science, Samsung Medical
Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku,
Seoul 135-710, South Korea.
Received May 7, 2007;
accepted after revision August 16, 2007.
Supported by grant SBRI C-A4-119-1 from the Samsung Biomedical Research
Institute and the 2005 research grant of Kangwon National University.
Abstract
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MATERIALS AND METHODS. The study was performed in 15 pigs using an internally cooled single electrode with a 1-cm electrically active tip under sonographic guidance. Twenty-three hepatic ablation zones abutting the gallbladder were analyzed in three phases on the basis of the distance of the electrode (group A, 0.5 cm; group B, 1.0 cm), electrode direction (perpendicular or parallel), and time of sacrifice (immediate or delayed [7 days after radiofrequency ablation]). We evaluated the gross changes, the depth of thermal injury, and the grade of abnormal microscopic changes in the gallbladder wall. Data analysis was performed on the basis of the Fisher's exact test
RESULTS. Discoloration and perforation were more frequent in group A (60%, 6/10, and 20%, 2/10, respectively) than in group B (25%, 2/8, and 0%, respectively, p > 0.05). Perforation was more frequent in the parallel direction and delayed phase (33.3%, 1/3, and 40%, 2/5, respectively) compared with the perpendicular direction and immediate phase (14.3%, 1/7, and 0%, respectively, p > 0.05). Depth of thermal injury showed a significant difference between group A and group B for full-thickness involvement (53.8%, 7/13, versus 0%, respectively, p < 0.05). Abnormal microscopic changes showed that parallel direction and immediate phase were more frequent with full-thickness involvement (71.4%, 5/7, and 71.4%, 5/7, respectively) compared with perpendicular direction and delayed phase (33.3%, 2/6, and 33.3%, 2/6, respectively, p > 0.05).
CONCLUSION. Hepatic radiofrequency ablation abutting the gallbladder can produce substantial thermal injury of the gallbladder wall, including perforation, especially when performed without a safe distance.
Keywords: gallbladder • liver • pig • radiofrequency ablation • safe distance • thermal injury
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Although radiofrequency ablation has been considered a safe technique, a broad spectrum of complications has been reported in several large series [8–10]. Collateral thermal damage after radiofrequency ablation of liver tumor has been reported in various organs [8–15]. Among them, the most important major complication due to thermal damage was perforation of the gastrointestinal tract and gallbladder. Several clinical reports have revealed complications of the gallbladder after radiofrequency ablation including acute cholecystitis and perforation of the gallbladder [3, 7, 8, 13, 16–19]. Also, injury of the gallbladder wall was inevitable for complete ablation of liver tumor adjacent to the gallbladder, which was frequently incomplete ablation because of the cooling effect of the bile during percutaneous radiofrequency ablation. However, to our knowledge, there has been no experimental study to assess the histopathologic features of gallbladder wall changes or evaluations of the predisposing factors for gallbladder wall injury after radiofrequency ablation.
The purpose of this study was to evaluate the histopathologic changes of the gallbladder wall surrounding radiofrequency ablation zones in pig livers and to assess the risk factors for thermal injury of the gallbladder wall in terms of the distance of the electrode from the gallbladder wall, electrode direction in relation to the gallbladder wall, and time of sacrifice of the animal after radiofrequency ablation.
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Fifteen Yorkshire pigs (one male and 14 females) were used in this study (mean weight, 29.8 kg; range, 25–38 kg) during a 1-year period. There were no focal lesions in the livers of the pigs. The pigs were anesthetized with an intramuscular injection of ketamine hydrochloride 20 mg/kg (Ketamine, Yuhan Yanghang) and xylazine hydrochloride 2 mg/kg (Rompun, Bayer Korea). After this induction, animals were intubated, and anesthesia was maintained with inhalation of 5 mL/min of 0.5% halogenated methyl ethyl ether. After adequate anesthesia was achieved, the right upper quadrants and epigastrium were shaved in the supine position, and the skin surface was sterilized. Both thighs were shaved, and two grounding pads (dispersive electrodes) were placed bilaterally.
Radiofrequency Ablation Procedure
All radiofrequency ablation procedures were performed with a sonography
scanner with a 4-1–MHz convex probe (Acuson Sequoia Gastrointestinal
512, Siemens Medical Solutions). A sonographically guided percutaneous
approach was used by one of three experienced radiologists. During the early
period of experiments, we experimented with radiofrequency ablation in pig
liver using alternative approaches including the percutaneous and
intraoperative methods. We thought heterogeneity of the treatment procedures
would influence the inhomogeneity results. In addition, we hoped to perform
radiofrequency ablation in pig liver in a similar environment as in human
liver using only the percutaneous approach. So, we chose the only percutaneous
approach for radiofrequency ablation in pig liver. The radiofrequency system
was a 480-kHz generator (Series CC-3, ValleyLab) capable of creating a maximum
power of 200 W with a monopolar internally cooled single electrode. The
electrode was equipped with two connectors (Luer LOC, ValleyLab) for inflowing
and outflowing iced distilled water coolant; this ensured a constant
temperature for the coolant of approximately 0–10°C. Circulation of
the cooling fluid was maintained with a pump (PE-PM Perfusion Pump,
ValleyLab). We used a single straight tip 17-gauge electrode with a 1-cm
electrically active tip. The power of the generator was set at 200 W and
maintained for 7 minutes on the basis of the hypothesis of induction of focal
irreversible coagulation necrosis when administered for 4–6 minutes
[20]. After making a small
incision in the skin, the electrode was advanced into the liver through an
intercostal or subcostal space, depending on an available acoustic window. The
active tip was then placed in the liver parenchyma adjacent to the
gallbladder.
Study Groups
The number of radiofrequency ablation zones per animal ranged from one to
three, with 23 ablation zones created in 15 pigs. The ablation zones were
created depending on the acoustic window of the pig liver: one ablation zone
in eight animals, which represented a poor sonic window due to the small
volume of liver adjacent to the gallbladder or the large amount of bowel gas
near the ablation zone; two ablation zones in six animals; and three ablation
zones in one animal. In the cases in which more than one ablation was
performed, there was enough distance, at least 1 cm, between ablation zones so
that they did not influence each other. Three phases of evaluation were
performed including distance of the electrode from the gallbladder wall (phase
1), electrode direction (phase 2), and time of sacrifice (phase 3)
(Table 1). We combined the
phases by random sampling during radiofrequency ablation. We first decided the
distance of the electrode from the gallbladder wall, then chose the electrode
direction, and finally made a decision regarding time of sacrifice during
radiofrequency ablation.
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Phase 1: 0.5 cm (group A) versus 1.0 cm (group B) distance of the electrode from the gallbladder wall—In this phase, the ablation zones were classified into two groups on the basis of the distance of the tip of the radiofrequency electrode from the gallbladder wall under real-time sonographic guidance: a group 0.5 cm from the gallbladder wall (group A, n = 13; mean distance, 0.49 cm; range, 0.36–0.51 cm) and a group 1.0 cm from the gallbladder wall (group B, n = 10; mean distance, 1.01 cm; range, 0.97–1.11 cm).
Phase 2: Perpendicular versus parallel direction of electrode in relation to the gallbladder wall—In group A and group B, radiofrequency ablation zones were subcategorized according to the electrode direction: those created based on a perpendicular direction to the long axis of the gallbladder (perpendicular direction, defined as group pp) and those based on a parallel direction along the long axis of the gallbladder (parallel direction, defined as group p) (Fig. 1A, 1B). In group A, six perpendicular (group App) and seven parallel ablation zones (group Ap) were created. In group B, five perpendicular (group Bpp) and five parallel (group Bp) ablation zones were created.
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Analysis of Gallbladder Wall Injury
Gross pathologic analysis—All animals were sacrificed using
IV injection of 24 mL of potassium chloride (150 mg/mL). Immediately after
euthanasia, the liver and gallbladder were exposed through a subcostal
incision. Before extracting the gallbladder, we obtained photographic images
of the abdominal cavity including the liver and gallbladder using a
high-resolution digital camera (Coolpix 5700, Nikon). After exposure, the
serosal side of the abutting gallbladder wall, the area surrounding the
ablation zone, and the adhesive liver parenchyma were grossly evaluated to
determine whether there was discoloration, defined as any change of color in
the gallbladder wall, or perforation, defined as bile leakage from the
gallbladder lumen or passing of wire through the gallbladder wall.
Histopathologic analysis—The hepatic parenchyma including the radiofrequency ablation zones and the gallbladder were excised and fixed in a 10% buffered formalin solution for a minimum of 24 hours for routine histologic processing. The formalin-fixed gallbladder was cut into 5-mm-thick slices and embedded in paraffin, and 6-µm-thick sections were serially cut and stained with H and E.
We analyzed the degree of injury to the body portion of the gallbladder wall for two factors: the depth of thermal injury in the gallbladder wall and the grade of microscopic change in the gallbladder mucosa. According to the depth of thermal injury, we classified the findings into four parameters: no involvement (defined as no abnormal microscopic change at the outer layer of the gallbladder wall), subserosa (defined as abnormal microscopic change up to the subserosal layer), muscle (defined as abnormal microscopic change up to the muscle layer), or full-thickness involvement (defined as abnormal microscopic change in all layers of the gallbladder wall).
Variable microscopic changes were evaluated in the gallbladder mucosa surrounding the ablation zones. The variables observed were as follows: hemorrhage, inflammation, fibrosis, necrosis, congestion, epithelial denudation, and epithelial degeneration. The grade of microscopic changes was rated according to the following four-point scale according to the number of involving mucosal folds and depth of microscopic changes up to the basal layer: 0, no change; 1, mild change (defined as involvement in tip of one or two mucosal folds without involvement of the basal layer); 2, moderate change (defined as involvement in one or two mucosal folds with involvement of the basal layer); 3, severe change (defined as involvement of at least three mucosal folds with involvement of the basal layer). All histopathologic analysis was performed by one experienced pathologist.
Statistical Analysis
The gross change in the serosal side of the gallbladder wall, the depth of
thermal injury in the gallbladder wall, and the degree of microscopic change
in the gallbladder mucosa for each group were compared using a frequency
number of variance. Values for p were calculated using the Fisher's
exact test. Data processing and analysis were performed using commercially
available software (SPSS, version 11.5, SPSS). Statistical significance was
defined as a p value of less than 0.05.
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Discoloration was more frequent in group A than in group B (Fig. 2A, 2B). The most serious complication of radiofrequency ablation was perforation, which was found in two of 10 ablation zones only in group A (Fig. 3); none was observed in group B.
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In group B, discoloration had the same frequency in the perpendicular and parallel direction procedures and immediate and delayed phases, but perforation was not seen in any case. No significant difference in discoloration and perforation was seen between the immediate and delayed phase and perpendicular and parallel direction in the two groups.
Microscopic Changes of the Gallbladder Wall
Depth of thermal injury of the gallbladder wall—Although
there were no abnormal changes at the outer layer of the gallbladder wall, or
only abnormal changes up to the subserosal layer of the gallbladder wall,
abnormal microscopic changes in the gallbladder mucosa were found in all
radiofrequency ablation zones. The variables of abnormal microscopic changes
in the gallbladder mucosa were noted in group A (n = 6) and group B
(n = 10) including the following: inflammation (n = 9),
epithelial degeneration (n = 7), congestion (n = 2),
epithelial denudation (n = 2), hemorrhage (n = 1), and
fibrosis (n = 1).
Thermal injury of the gallbladder wall was significantly more frequent in groups with 0.5-cm distance compared with others on the basis of abnormal microscopic changes in the full-thickness layer (Fig. 4A, 4B) and no abnormal changes in the outer layer of the gallbladder wall (p < 0.05) (Table 3).
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Although cases with up to subserosal involvement had a higher frequency in the perpendicular direction compared with others in groups A and B, full-thickness involvement representing severe thermal injury had a higher frequency with the parallel direction procedures compared with others.
The cases with up to full-thickness involvement of the gallbladder wall were more frequent (71.4%, 5/7) in the immediate phase group compared with others (33.3%, 2/6) in group A; however, none was observed in group B. By contrast, cases with up to subserosal involvement of the gallbladder wall were more frequent in the acute phase than others of both groups A and B (Table 3).
Variables of abnormal microscopic changes of the gallbladder mucosa—The variables studied of abnormal microscopic changes in the gallbladder mucosa in the two groups are described in Table 4. Mucosal hemorrhage, inflammation, fibrosis, and necrosis were of a higher grade in groups A compared with group B. However, pairwise comparisons did not show significant differences between the two groups.
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Collateral thermal damage to the gallbladder by thermal convection from radiofrequency ablation zones can theoretically develop after radiofrequency ablation of a hepatic tumor adjacent to the gallbladder [3, 9, 13, 17]. However, clinical reports of symptomatic cholecystitis or gallbladder perforation after radiofrequency ablation of tumor abutting the gallbladder have been very limited, as in our survey, because fluid content within the gallbladder lumen plays a role in dissipation of heat around the gallbladder fossa. Chopra et al. [13] reported that radiofrequency ablation of hepatic tumors adjacent to the gallbladder wall was safe and feasible because symptoms related to the gallbladder were self-limited. Adhesions due to previous surgery or percutaneous therapy or chronic cholecystitis may be a potential risk factor for injury to the gallbladder [8, 16, 34]. Previous reports consider methods to minimize injury of the gallbladder wall such as open or laparoscopic guidance or nonthermal ablation methods such as percutaneous ethanol injection [8]. However, the pathologic changes of the gallbladder wall close to the radiofrequency ablation zone have not been established, and the safe distance to minimize collateral thermal injury has not been determined.
The current study showed that radiofrequency ablation of the liver abutting the gallbladder could cause significant thermal damage to the gallbladder wall. However, perforation was noted only in group A with 0.5-cm safe distance. Our results support previous studies claiming that a safe distance is at least 1 cm from the gallbladder [18, 19, 34].
On the basis of the current results, we realized that all cases that revealed perforation were not found in the immediate phase but rather the acute phase (7 days after radiofrequency ablation). Our data suggest that perforation may be sequelae of the acute healing process of the thermally injured gallbladder. These results appear to be consistent with previous studies claiming that thermal injury may require time for progressing to bowel perforation [8, 11]. Therefore, to avoid delayed perforation of the gallbladder, clinical and imaging follow-up is mandatory 1–2 weeks after radiofrequency ablation of liver abutting the gallbladder wall, especially if there is gallbladder wall thickening on imaging studies performed during or immediately after the procedure.
We found the degree of thermal injury was related to the safe distance, on the basis of the microscopic analysis of full-thickness thermal injury. The rate of full-thickness thermal injury was significantly higher in group A (without safe distance) compared with group B (with safe distance). In addition, full-thickness thermal injury was more severe in the immediate phase group compared with the delayed phase and in the parallel direction compared with the perpendicular direction, although statistical significance was not proven. Our results suggest that full-thickness involvement of the gallbladder wall in the immediate phase could result in delayed perforation such as sequelae of the acute healing process of thermally injured gallbladder.
A previous report suggested that radiofrequency ablation of hepatic tumors adjacent to the gallbladder was potentially safe regardless of whether the orientation was perpendicular or parallel relative to the gallbladder wall [13]. Our findings suggest that electrode placement perpendicular to the gallbladder wall may be safer than in the parallel direction, but we could not find any literature to prove this hypothesis. We suppose that the tip of the electrode in the perpendicular direction group could move away from the gallbladder wall because of respiration during the ablation procedure or that, in contrast to the parallel direction exposing the gallbladder wall to a higher surface of the electrode, in the perpendicular direction only the extreme tip (i.e., a cool tip in the straight type of electrode used in this study) is close to the gallbladder wall.
Severe thermal injury of the gallbladder mucosa was found in group A, with parallel orientation to the gallbladder wall, and during the delayed phase. Surprisingly, the abnormal microscopic changes of the gallbladder mucosa were found in all of the radiofrequency ablation zones studied, even in cases with no abnormal thermal injury at the outer layer of the gallbladder wall or up to subserosal involvement. Some authors [35] have presented hypotheses regarding the pathogenesis of distal biliary lesions at a distance from the ablation zone: either the biliary secretions form an electric current conduction or the heat generated by the ablations is spread out by convection into the bile ducts. On the basis of these hypotheses, thermal insult by an electric current might be possible at a distance from the gallbladder mucosa without any changes in the outer layer of the gallbladder wall.
Our study has some limitations. First, the number of ablation zones in each group was not sufficient, especially according to the time of sacrifice (immediate or delayed phase) and electrode direction (perpendicular or parallel direction). Second, the long-term prognosis was not investigated for thermal injury of the gallbladder wall including perforation because of the short-term (7 days after radiofrequency ablation) follow-up of this study. Third, radiofrequency ablation was performed in the normal pig liver. The lack of a good tumor model and cirrhotic liver parenchyma limits the ability of our study to fully explore experimentally. The normal liver parenchyma will vary in thermoconduction of heat from tumor model and cirrhotic liver parenchyma because of differing patterns of vascularity and thermoconductive properties. Vessels in cirrhotic liver parenchyma will undergo shrinkage, so the heat sink effect of shrinkage on a vessel will decrease compared with patent vessels of normal liver parenchyma. Thus, the study results could be changed in clinical cases of underlying cirrhosis in human patients. Finally, this study used the same type of radiofrequency device and the same ablation parameters including duration of ablation. Therefore, the variability of thermal injury to the gallbladder wall as it relates to various radiofrequency devices and variable duration was not investigated. In particular, we performed radiofrequency ablation using only a 1-cm electrically active tip, so we would neglect the difference of the volume of thermal injury using a 2- or 3-cm electrically active tip. These probes ablate a larger volume of tissue compared with the 1-cm exposed tip. It could be necessary to keep more than a 1.0-cm safe distance to avoid thermal injury in radiofrequency ablation using these probes.
In summary, thermal injury to the gallbladder after radiofrequency ablation of the liver was more severe, especially if the distance between the electrode and the gallbladder wall was 0.5 cm or the direction of the electrode was parallel to the gallbladder wall. The resulting perforation appeared to be a delayed (up to 7 days) process rather than an immediate complication. Full-thickness injury of the gallbladder wall was more frequent in the group without a safe distance on microscopic analysis. Consequently, the safe distance (about 1 cm) of an electrode from the gallbladder wall may be a useful technical tip to minimize the degree of thermal injury of the gallbladder wall during radiofrequency ablation using a 1-cm electrically active tip.
Acknowledgments
We thank Bong Geun Choi for statistical analysis and Kwang Sun Min for
pathologic analysis in this article.
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