Management of small renal tumors with radiofrequency ablation☆

RF ablation 

RF ablation effectively uses heat to destroy living tissue. This technology is Food and Drug Administration approved for ablation of aberrant atrioventricular conduction pathways for patients with Wolf-Parkinson-White syndrome21 and for treating soft-tissue lesions in the liver.22, 23

RF ablation works by converting RF waves into heat, resulting in thermal damage to parenchymal tissue. For solid organ tumor ablation, thin (14 to 21-gauge) RF electrodes are introduced by way of laparotomy or percutaneously or laparoscopically to the desired location, under visual or radiologic guidance (ultrasonography, computed tomography, or magnetic resonance imaging). RF electrodes are electrically insulated along all but the distal portion of the shaft or electrode tip. Typically, power (5 to 120 W) is delivered to the electrode by an RF generator. Alternating current (450 to 1200 kHz) passes from the electrode tip to the surrounding tissues with a current density proportional to 1/r2 (r = radius) from the electrode. This current generates ionic or molecular agitation, thereby causing a collision of particles in accordance with the frequency of energy waves generated.21 These collisions generate frictional heating in a localized area around the core, resulting in a hot electrode tip with temperatures reaching beyond 100°C. Heat conduction is dependent on the electrode configuration, time of ablation, surface area of the active electrode, RF current, and distance from the electrode.24 Using monopolar electrodes, a zone of conductive heat may be created within 1.0 to 1.5 cm of the electrode-tissue interface.21

When the temperature of tumor cells is elevated to greater than 70°C, direct cytologic destruction occurs.25, 26 At these elevated temperatures, lipid bilayers of the plasma membrane separate, intracellular and extracellular proteins denature, and the basic cellular and tissue architecture is lost.27 Cellular contents subsequently extrude and form a coagulum. RF results in tissue desiccation, with the movement of intracellular water out of cells and extracellular water out of tissue. In the first few hours, reactive changes, including cellular edema and localized inflammation, are predominantly seen.21, 24 Approximately 3 to 7 days after RF ablation, thermally damaged tissue reorganizes to resemble coagulative necrosis with inflammatory cells. Two months after RF application, complete effacement of epithelial tissue with only stroma remaining has occurred.24

RF destroys tissue by raising the tissue temperatures above a critical level by direct and conductive heating for an adequate period, as determined by the temperature-time curve for tissue necrosis.28 If the temperature of tissue is less than 55°C, or greater than 55°C for an inadequate amount of time, an incomplete thermal lesion may be created.25, 27 The tissue temperature decreases as the distance from the electrode increases (1/r4).

The size of RF thermal lesions is dependent on the amount of RF energy delivered, the time of the RF energy delivery, and the thermal properties of the tissue, especially tissue impedance. In the initial studies with conventional (“dry”) RF ablation, tissue impedance was found to dramatically increase with the production of charred tissue around the electrode.24, 27, 29

Several innovations have been used to enhance the size of the RF lesion. Bipolar electrodes or monopolar electrodes with multiple hooks may both enlarge and better define the treated zone. Retractable insulating shields allow for a longer electrode tip and a larger zone of effect.29 Thermocouples located on electrodes monitor the rise in temperature and enable a more gradual increase in the current delivered to the tissues. During conventional RF ablation, tissue destruction around the electrode resulted in increased impedance (often greater than 140Ω), thereby limiting the size of the RF lesion. This rise in impedance may be overcome by the use of an electrolyte coupler, or the “wet” RF ablation technique. The wet technique involves hollow electrodes through which a conducting solution is infused into tissues before and during RF application to enhance the tissue conductivity. As a result, the current density and, consequently, the power source are spread further into the region surrounding the infused interstitial electrolyte solution. Several studies have demonstrated that hypertonic saline is an effective conducting solution.21, 24, 29 In a study comparing techniques, Hoey et al.22 demonstrated larger lesions in myocardial tissues with wet RF (range 2.5 to 22.8 cm3) than with conventional RF ablation (range 0.06 to 0.93 cm3). The size of the lesions with wet RF techniques is governed primarily by electrode geometry, the conductivity of the electrolyte infusion, and the duration and amount of RF energy delivered.24

Thermal destruction mediated by RF is altered by vascular flow.24 The degree of attenuation of RF energy can be calculated using the bioheat transfer equation.30 The quantity of conventionally used RF energy theoretically does not produce enough heat per unit volume of tissue to have an ablative effect on vessels larger than 2 mm in diameter. Blood flow acts as a heat sink and dissipates the thermal energy before the blood vessel’s intima reaches ablation temperatures. Although major arteries and veins should be immune to conventional RF, the effectiveness of RF ablation on well-vascularized tumors has not been ascertained. Some investigators have advocated temporary ischemia to increase the effectiveness of RF ablation, as reported with the Pringle maneuver in the liver.23 However, the need for temporary ischemia may only be theoretical and has not been firmly established in clinical investigations. With use of 50 to 150 W of RF energy through a single electrode, the heat sink of vessels larger than 2 mm in diameter can theoretically be overcome.24

RF ablation of solid organ tumors 

RF ablation has been used to destroy hepatic masses and osteoid osteomas thermally in animals and humans.23 RF has been used by neurosurgeons for both tumor ablation and treatment of functional neurologic conditions. In several studies, RF has been demonstrated to be a relatively safe, well-tolerated, and minimally invasive treatment for hepatic masses.23, 31

RF energy has been used for treatment of benign prostatic hyperplasia.27, 29, 32, 33 Initial studies with conventional RF for benign prostatic hyperplasia were limited by the small size of the RF lesions. Charring of prostatic tissues with ensuing increases in the electrical impedance at the electrode tip limited the lesion size created with standard RF electrodes.29 Hypertonic saline-enhanced RF electrodes have been used to create larger lesions in animal studies.29

RF ablation was also examined for percutaneous transperineal ablation of prostate cancer in patients before radical prostatectomy.27 RF lesions were visible as hypointense foci on T1-weighted, gadolinium-enhanced, magnetic resonance imaging. Histologically, RF lesions appeared to be nonviable tissue in 19 of 21 cases.

Effect of RF ablation on animal kidneys 

The effect of RF on renal tissues have been studied in porcine and rabbit species. The need to target specific areas for RF ablation has resulted in the use of these animals rather than rodents for pilot experiments.

The initial feasibility studies using conventional 17-gauge monopolar RF probe electrodes were performed on porcine kidneys.17 RF probes were percutaneously placed using magnetic resonance imaging guidance into either the upper or lower pole. RF energy was applied for 10 minutes using a 120-W RF generator (model RFG-3C, Radionics, Burlington, Mass) at 500 kHz. On the immediate postprocedure imaging study, RF lesions appeared hypointense in 10 of 10 cases on T2-weighted images compared with the renal cortex. Histologic examination revealed a 7 to 14-mm RF lesion, characterized by shrunken nuclei, collapsed tubules, and disorganized tissue architecture.

In another study, bilateral renal RF ablation was laparoscopically or percutaneously performed in 11 pigs.34 Conventional RF was performed with 8F electrodes in a spreading array of 8 to 10 curved metallic wires. RF energy generated from a prototype unit (Radiotherapeutics, Mountainview, Calif) was applied for 10 minutes. Power was serially increased by 10 W/min from 55 W for 5 minutes until increased tissue impedance prevented additional RF ablation. Immediate gross pathologic examination revealed a blanched discolored radiolesion. Histopathologic analyses of these radiolesions showed an initial (7 days) inflammatory response and extensive coagulation necrosis and a later (90 days) nearly complete resorption of the necrotic lesion with diminishing inflammation.35

Polascik et al.36 performed wet RF ablation on small papilloma (VX-2) tumors implanted beneath the capsule of 18 rabbit kidneys. Hypertonic (14.6%) saline was infused through the central lumen of a 26-gauge monopolar electrode before and during the application of 50 W of RF energy (RFT system, U.S. Surgical, Norwalk, Conn) at 500 kHz for 30 or 45 seconds. Conventional gray-scale ultrasonography allowed real-time visualization of the ablative process, because the applied RF energy and saline infusion caused a bubbling effect in the area of the treatment that was sonographically apparent as a region of geographically increasing echogenicity. Power Doppler ultrasonography demonstrated no perfusion of the tumor after ablation. The average lesion diameter after the 30 and 45-second treatments was 1.4 and 1.8 cm, respectively, determined after the rabbits were killed 18 hours after RF ablation. Histologic examination revealed marked coagulative necrosis, acute inflammation, hemorrhage, edema, and a hemorrhagic rim in the marginal zone.

In a complementary study, a detailed time course of the effect of wet RF on normal rabbit renal tissues was performed.37 Hypertonic saline (14.6% NaCl, 2 mL/min) was used before and during RF ablation. RF energy (50 W) at 475 kHz (modified ATAKR RF generator, Medtronic, CardioRhythm, San Jose, Calif) was delivered by way of monopolar hypertonic saline-enhanced electrodes for 1 to 2 minutes. Histopathologic examination revealed that the average lesion for the 1 and 2-minute RF treatment was 7 and 10 cm3, respectively. Complete coagulative necrosis was observed within the ablated areas 1 to 3 days after treatment. After longer periods (21 to 54 days), radiolesions evolved into well-demarcated zones with complete effacement of tubular epithelium and destruction of glomeruli. No damage was seen to adjacent tissue, suggesting that RF ablation produces circumscribed areas of destruction.

These study results, although preliminary, are encouraging. It would appear that hypertonic saline reduces the typical rise in impedance created by conventional RF ablation, allowing for more energy input and production of larger lesions. The time required for saline-enhanced RF (30 seconds to 2 minutes) is also considerably shorter than that typically used for conventional RF ablation (6 to 12 minutes).

RF ablation and human renal tumors 

RF ablation for renal masses was initially described in combination with radiotherapy, chemotherapy, and embolization in the treatment of large, metastatic renal masses.38, 39 The effect of RF energy on these tumors was not immediately quantifiable, because it was performed in combination with other therapeutic modalities. Furthermore, no histologic confirmation of the treatment effect was obtained.

RF ablation as a primary treatment of human renal tumors was first described by Zlotta et al.33 Bipolar conventional RF was used on four nephrectomy specimens to examine the effect of RF ablation on normal renal tissue, as well as on renal tumors. The renal artery was cannulated ex vivo, and the kidneys were perfused with warmed (37°C) saline to mimic physiologic conditions. A total of 50 W of RF energy from a RITA generator (Mountainview, Calif) was delivered at 460 kHz for 12 minutes using bipolar electrodes. The temperatures recorded by thermocouples ranged from 123°C at the electrode to 72°C in the tissue between the electrodes. Macroscopically, the RF lesions were large (2 × 3 × 2.5 cm), grossly discolored, and demarcated from the surrounding tissue. Microscopic analysis showed intense stromal and epithelial edema with marked hypereosinophilia and pyknosis. RF energy had similar effects on both tumor and normal renal tissue.

Conventional RF ablation was then performed intraoperatively on 2 patients.33 In the first patient, the RF electrodes were inserted into the renal tumors and 12 W of RF energy was delivered for 12 minutes just before nephrectomy. The histologic changes were similar to those seen in the ex vivo experiment. In the second patient, RF ablation was performed 1 week before nephrectomy under ultrasound guidance. A repeated computed tomography scan performed immediately before surgery showed no enhancement of this previously enhancing tumor. Histopathologic analysis revealed extensive coagulative necrosis in a 2 × 2 × 1.5-cm3 sphere around the needle electrode.

McGovern et al.19 anecdotally reported the successful treatment of a suspicious renal lesion with conventional image-guided monopolar RF ablation (Cosman Coagulator CC-1, Radionics, Burlington, Mass) in an elderly patient who refused surgery. Follow-up imaging at 1 and 3 months revealed persistent nonenhancement of the treated region. No residual or recurrent tumor was noted in the short follow-up period. In a larger series of 8 patients with biopsy-proven RCC from the same group, follow-up imaging at 1, 3, and 6 months showed that peripheral exophytic tumors (5 of 5) did not enhance after RF.40 Smaller lesions (less than 3 cm) were most amenable to a single RF application, and larger lesions required multiple RF treatments. Centrally located renal tumors (1of 3) were not as successfully treated with RF.

In a National Cancer Institute-sponsored pilot study, 11 small (less than 3 cm) RCCs in 4 patients were treated percutaneously with monopolar conventional RF.41 The tumors were treated with RF energy of 26 W at 480 kHz (RITA, Mountainview, Calif) for 5 minutes. On follow-up color Doppler ultrasonography, the blood flow to each tumor evident before ablation was not visualized after RF ablation. Histopathologic analysis revealed a loss of nuclear detail and nonvisualization of nucleoli in 10 of 11 tumors. “Wet” RF ablation has been performed on 17 patients with radiographically diagnosed renal masses, who were scheduled for definitive extirpative surgery, at the University of Miami.42 An ERBE generator was used at 120 W with hypertonic saline infusion (14.6% NaCl, 2 mL/min) through a single electrode for 60 to 180 seconds, depending on tumor size. Lesions averaged 1.5 to 3.0 cm in diameter, and microscopic examination revealed tumor cell death primarily by coagulative necrosis with peripheral zones of hemorrhagic necrosis. Gross lesion size, however, was difficult to discern in certain tumor types. The thermal spread of energy appeared to be more uniform in “homogeneous” tissue. The histopathologic comparison of ablated with nonablated tumor areas revealed that ablated tumor areas had altered histologic characteristics, including elongated nuclei and cellular staining patterns, giving the appearance of advanced Fuhrman grade, and pseudosarcomatoid patterns.42 Pathologic “misinterpretation” may occur if untreated tumor is not available, implying that preablation biopsies may be necessary to avoid overgrading of tumors.

Comment 

Application of RF to renal masses is new and developmental. The kidney may be an excellent target for RF ablation, because it is anatomically separate from surrounding tissue by Gerota’s fascia. Fat also provides a protective insulating buffer from the colon. Laparoscopic and percutaneous approaches to the kidney are familiar to the urologist and may be performed under ultrasound guidance in a same-day surgery setting.

Initial reports have examined the effectiveness of RF in thermally ablating peripheral renal tissue and tumors. Both conventional and wet RF techniques demonstrate the ability to safely and consistently create discrete lesions in animals and in humans.33, 34, 36, 41 A representative pre-RF and post-RF ablation computed tomography scan demonstrating the effects of RF on a renal mass is shown (Fig. 1). RF produces immediate macroscopically discolored lesions (Fig. 2A). Acute histologic evaluation of conventional RF-treated tissues is consistent with thermal desiccation (Fig. 2). Over time, the tissue dies following the thermal injury by coagulative necrosis, and a scar may become grossly evident. In the limited follow-up of these studies, no tumor recurrence within the RF-ablated lesions has been seen. These early data suggest the feasibility of RF ablation in treating renal masses, but long-term studies are necessary to determine overall efficacy.

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FIGURE 1. Imaging of RF ablation. (A) Contrast-enhanced computed tomography scan through lower pole of left kidney revealing a 5-cm enhancing mass anteriorly before RF ablation and (B) a somewhat larger, nonenhancing mass of nonviable tissue 1 month after RF ablation.

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FIGURE 2. Macroscopic RF ablation. RF electrodes were inserted percutaneously into a human kidney under laparoscopic guidance. An ERBE RF surgical generator (120 W RF, 475 kHz) in the power control mode was used and 2 mL/min of 14.6% NaCl solution was infused through an 18-gauge insulated needle with a 1-cm exposed distal tip. The scheduled nephrectomy after RF ablation was performed, and (A) gross lesions are visible on tumor tissue (arrow). The kidney was then fixed in formalin, and the tissues were sectioned and subjected to hematoxylin-eosin histologic examination. (B) Microscopic hematoxylin-eosin staining for RF-treated normal renal tissue. (C) Acute effects of RF ablation on human renal tumors with distinct demarcation between zones of nonablated (dark arrows) and RF-ablated tumor tissue (light arrows).

Comparative analyses of the effect of RF on kidneys are hampered by technical differences among various studies. Histologic confirmation of tissue destruction was not consistently obtained at similar points after RF treatment. The variation in electrode characteristics (monopolar versus bipolar, length of active probe, gauge, conformation, hooks versus arrays), RF energy characteristics (type of RF generator, amount of energy supplied, duration of treatment, tissue temperature), and technique (conventional versus saline enhanced) must be considered when examining the data from each study.

The conventional technique may be limited by the size of the lesion, because of the increased tissue impedance. Several probe placements and heating cycles are often used to achieve sizable lesions with monopolar probes.33, 34 Use of triple-hook and multihook needles (LeVeen electrodes) may allow for larger lesions.29, 34 Finally, 6 to 12 minutes of conventional RF have been used for tissue ablation. On the other hand, saline-enhanced RF ablation uses an electrolyte coupler, which helps maintain a low-tissue impedance and shorter RF application times (30 seconds to 2 minutes).24, 29, 36 In studies with hepatic, prostatic, and renal tissue, saline-enhanced RF resulted in much larger lesions than with conventional RF.21, 27, 29, 36, 37 In reports with renal tissue, short applications (30 seconds to 2 minutes) of saline-enhanced RF resulted in a 2-cm diameter zone of tissue destruction. In preliminary studies, saline-enhanced RF appeared to have different effects on medullary and cortical areas and on glomeruli and tubules.36, 37

Real-time imaging of renal lesions may allow RF energy to be delivered in a more precise manner. The true edge of RF lesions can be difficult to visualize.34 The hyperechoic outgassing during RF ablation is produced by higher temperatures than is required for cell death at the peripheral edge of the lesion. RF lesions may be detected as a loss of contrast enhancement or altered echogenicity.33, 36, 37, 43

Potential complications associated with RF ablation include urinary extravasation and hemorrhage. RF has been shown to ablate soft tissues consistently with adequate hemostasis, because of the small (0.46 to 1.7 mm) size of the electrodes. Furthermore, the hot electrode tip is thought to cauterize tissue in the probe tract and minimize bleeding after withdrawal. However, in one study, 3 of 10 RF procedures were complicated by subcapsular hematomas.17 Additional risks of percutaneous RF include radiodermatitis, skin burns, injury to bowel, and potential for dissemination of neoplastic cells, either hematogenously or along the needle tract.

These data suggest the feasibility of applying RF energy to ablate renal lesions. However, several critical issues remain to be resolved before widespread application of RF ablation for renal tumors. For each RF generator, electrode configuration, and type, ablation protocols must be evaluated to produce reproducible RF lesions with respect to lesion size, morphology, and location. For a more detailed description of the various electrodes, the reader is encouraged to refer to the fine review by Djavan et al.44 The RF lesion created must correlate histologically with cell kill and necrosis. Furthermore, the homogeneity of cell death within the RF lesion must be explored. Treatment protocols can then be customized for each unique tumor location, size, and configuration.

Better intraoperative monitoring modalities (temperature sensors, temperature velocity parameters, cool down phase times, and tissue resistivity sensors) need to be incorporated to ensure completeness of RF ablation. Intraoperative visualization and real-time imaging technologies need to be optimized to monitor the effectiveness of each treatment and help dictate the need for additional RF treatments.

Conclusions 

Recently, NSS has been established as a viable alternative for small (less than 4 cm) renal tumors.11, 41, 45 Initial reports indicate that RF energy may be successfully used to ablate renal tissues in vitro. In animal studies, RF energy has shown the ability to create discrete lesions in the kidney. Preliminary reports have demonstrated the ability of RF to ablate human kidney tumors. The long-term cancer control efficacy of RF ablation in humans is unknown.46, 47 This technology requires additional study, before larger scale human trials.