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Perspective |
1
Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline
Ave., Boston, MA 02215.
2
Department of Radiology, Massachusetts General Hospital, 32 Fruit St., Boston,
MA 02114.
Received April 26, 1999;
accepted after revision July 19, 1999.
Address correspondence to S. N. Goldberg.
Introduction
 Top Introduction Induction of Coagulation...Sources of Thermal EnergyHeat-Tissue InteractionsSources of Heat LossDiagnostic Imaging for Thermal...Trends for Thermal Ablation...ConclusionReferences |
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Many similarities exist among the thermal methods of ablation. However, the individual techniques used for destruction are often discussed only within the framework of that particular technology (RF, laser, and so forth), rather than from a global perspective of looking at thermal therapy as a whole. This outlook may be shortsighted because many aspects of thermal ablation have been independently rediscovered. For example, innovations to increase energy deposition, such as reducing excess heat near the thermal source by internal cooling, have been shown useful for many techniques including RF, laser, high-intensity sonography, and microwave [18, 19, 20, 21]. Additionally, the biophysical limitations that prevent adequate tumor ablation are innate to tumor biology and will pose similar problems for all thermal ablation methods. A key example is the effect of tissue blood flow that limits coagulation in vivo [22, 23, 24, 25]. Furthermore, issues related to monitoring of ongoing ablation procedures apply equally to all these methods, and imaging findings are remarkably similar at follow-up.
Therefore, this perspective proposes a unified framework for discussing the various aspects of all thermal ablation therapies as they relate to the treatment of focal malignancies. This framework is based loosely on Pennes' [26] bioheat equation, which takes into account the factors that influence tissue heating (Appendix 1). Briefly, the extent of coagulation necrosis induced in a given lesion is equal to the energy deposited, modified by local tissue interactions, minus the heat lost before inducing thermal damage.
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Induction of Coagulation Necrosis
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TopIntroductionInduction of Coagulation...Sources of Thermal EnergyHeat-Tissue InteractionsSources of Heat LossDiagnostic Imaging for Thermal...Trends for Thermal Ablation...ConclusionReferences |
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Cellular homeostasis can be maintained with mild elevation of temperature to approximately 40°C. When temperatures are increased to 42-45°C (hyperthermia), cells become more susceptible to damage by other agents such as chemotherapy and radiation [27, 28]. However, even prolonged heating at these temperatures will not kill all cells in a given volume because continued cellular functioning and tumor growth can be observed after relatively long exposure to these temperatures. When temperatures are increased to 46°C for 60 min, irreversible cellular damage occurs [29]. Increasing the temperature only several degrees to 50-52°C markedly shortens the time necessary to induce cytotoxicity (4-6 min) [30]. Between 60° and 100°C, near instantaneous induction of protein coagulation that irreversibly damages key cytosolic and mitochondrial enzymes and nucleic acid—histone complexes occurs [31, 32]. Cells experiencing this extent of thermal damage most often, but not always, undergo coagulative necrosis over the course of several days. The term "coagulation necrosis" has been used to denote irreversible thermal damage to cells, even if the ultimate manifestations of cell death do not fulfill the strict histologic criteria of coagulative necrosis. Temperatures greater than 105°C result in tissue boiling, vaporization, and carbonization. These processes usually retard optimal ablation because of a resultant decrease in energy transmission [30]. Thus, a key aim for ablative therapies is achieving and maintaining a 50-100°C temperature range throughout the entire target volume.
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TopIntroductionInduction of Coagulation...Sources of Thermal EnergyHeat-Tissue InteractionsSources of Heat LossDiagnostic Imaging for Thermal...Trends for Thermal Ablation...ConclusionReferences |
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For most methods of thermal ablation, energy is applied percutaneously with needle-shaped applicators. These high doses of energy usually concentrate around the applicator and require heat conduction through the tissue from this local thermal reservoir to coagulate deeper tissues. For RF, radio waves emanate from the noninsulated distal portion of the electrode. Heat is produced by resistive forces (i.e., ionic agitation) surrounding the electrode as the radio waves attempt to find their ground, usually a foil pad attached to the patient's back or thighs. For microwave, needle-shaped electrodes function as an antenna that concentrates energy around the applicator and heats the tissue by friction, as polar molecules attempt to align with the electromagnetic field. For photocoagulation, thin optical fibers that conduct laser energy are placed through needles positioned in the tumor. These bare fibers transmit the intense light into the tissue, where the light is converted to heat. For both microwave and laser, the depth of energy penetration can be altered by altering the frequency of the energy source. Percutaneous probes containing multiple small piezoelectric transducers can deposit sufficient sound energy to heat adjacent tissues. Another potential application of sonographic energy has been incorporated into extracorporeal systems of energy delivery. These systems rely on focusing intense energy from an external sonographic source. Unfortunately, the maximum size for a single ablative focus has thus far approximated a grain of rice; therefore, complex imaging-guided systems are necessary to adequately treat larger areas [36]. However, improvements in technology may ultimately allow the treatment of larger foci.
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TopIntroductionInduction of Coagulation...Sources of Thermal EnergyHeat-Tissue InteractionsSources of Heat LossDiagnostic Imaging for Thermal...Trends for Thermal Ablation...ConclusionReferences |
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Several strategies have been developed to improve tissue—energy interactions for thermal ablation therapy, with the goal of increasing the region of induced coagulation to enable the treatment of most clinically relevant tumors (i.e., those measuring >1-2 cm in diameter) (Table 1). These strategies can be classified as those that permit an increase in overall energy (amount and rate) deposited, those that improve heat conduction within the tissue, and those that decrease tumor tolerance to heat.
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Increasing Energy Deposition
A common method for increasing energy deposition throughout an entire
lesion has been to repeatedly insert multiple RF, laser, and microwave probes
into the tissue to increase the diameter of induced coagulation
[3,
5,
7,
36]. This approach is both
time-consuming and difficult to use in the clinical setting, particularly
because multiple overlapping treatments must be performed in a contiguous
fashion (in all three dimensions) to destroy the entire lesion. Simultaneous
application of energy using arrays can reduce the duration of therapy
[42,
43]. However, the precise
positioning of multiple probes can be technically challenging. The development
of umbrella RF electrodes with multiple hooked arrays has overcome some of
these problems and has enabled the creation of larger zones of coagulation
[3,
9,
44].
Much recent development has centered on strategies that preferentially cool tissues nearest the probe in an attempt to increase overall energy deposition. Internally cooled electrodes have been used with RF, microwave, high-intensity sonography, and laser [18, 19, 20, 21]. For internally cooled devices, two internal lumens permit the delivery of chilled perfusate to the tip of the electrode and allow the warmed effluent to be removed to a collection unit outside the body. This procedure causes a heat-sink effect that removes heat closest to the electrode (Fig. 1). Pulsing of energy is another strategy that has been used with RF and laser to increase the mean intensity of energy deposited. When pulsing is used, periods of high energy deposition are rapidly alternated with periods of low energy deposition. If a proper balance between high and low energy deposition is achieved, preferential tissue cooling occurs adjacent to the applicator during periods of minimal energy deposition without significantly decreasing heating deeper in the tissue. Thus, even greater energy can be applied during periods of high energy deposition, enabling deeper heat penetration and greater tissue coagulation [45, 46]. Combination of both internal cooling and pulsing has been shown as synergistic with even greater tissue destruction observed than with either method alone [47].
Improved Tissue Heat Conduction
Improved heat conduction within the tissues by injection of saline and
other compounds has also been proposed
[48,
49,
50]. The heated liquid spreads
thermal energy farther and faster than heat conduction in healthy
"solid" tissue. An additional potential benefit of simultaneous
saline injection is that it increases tissue ionicity, thereby enabling
greater current flow. Similarly, amplification of current shifts with iron
compounds injected or deposited in the tissues before ablation has been used
for RF and microwave [50].
Another primary factor that can alter the extent of coagulation necrosis is tissue composition because heat conducts through different tissues at various rates [4, 51]. For example, poor thermal conduction has been documented for bone compared with muscle [51]. This fact has been an advantage in the treatment of hepatocellular carcinomas and vertebral body lesions. Livraghi et al. [4] have described the "oven effect" in which cirrhotic tissue insulates hepatocellular carcinoma nodules and increases temperatures within the targeted tumor during RF therapy. Dupuy et al. [51] have shown that cortical bone also serves as an insulator, enabling treatment of vertebral body lesions without damaging the spinal cord.
Strategies That Decrease Tumor Tolerance to Heat
Strategies that decrease tumor tolerance to heat have been proposed but are
not yet well studied. Theoretically, previous insult to the tumor cells by
cellular hypoxia caused by vascular occlusion or antiangiogenesis-factor
therapy (i.e., endostatin) or prior tumor cell damage from chemotherapy or
radiation could be used to increase tumor sensitivity to heat. Synergy between
chemotherapeutic agents and hyperthermic temperatures (42-45°C) has
already been established [27,
28].
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TopIntroductionInduction of Coagulation...Sources of Thermal EnergyHeat-Tissue InteractionsSources of Heat LossDiagnostic Imaging for Thermal...Trends for Thermal Ablation...ConclusionReferences |
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On the basis of these observations, several strategies for reducing blood flow during ablation therapy were proposed. Total portal inflow occlusion (Pringle's maneuver) has been used but requires open laparotomy [22]. Angiographic balloon occlusion can be used but may not prove adequate for intrahepatic ablation because of the dual hepatic blood supply with redirection of compensated flow [22]. Embolotherapy before ablation with particulates that occlude sinusoids such as a gelatin sponge (Gelfoam; Upjohn, Kalamazoo, MI) or iodized oil (Lipiodol; Roissey-Charles-de-Gaullle, France) may overcome this limitation [52]. Pharmacologic modulation of blood flow and antiangiogenesis therapy are theoretically possible but should currently be considered experimental.
Diagnostic Imaging for Thermal Ablation Therapy
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TopIntroductionInduction of Coagulation...Sources of Thermal EnergyHeat-Tissue InteractionsSources of Heat LossDiagnostic Imaging for Thermal...Trends for Thermal Ablation...ConclusionReferences |
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Diagnostic Imaging for Lesion Targeting
Multiple imaging techniques (sonography, CT, and MR imaging) can be used to
guide the percutaneous placement of thermal energy applicators into the
selected target [1,
2]. Because in most cases
adequate lesion conspicuity and visualization of the applicator can be
achieved with any of these methods, the choice of imaging technique is often
dictated by personal preference or research interests. Most imaging-guided
thermal ablation procedures have thus far been performed with sonography (Fig.
2A,
2B,
2C). Benefits claimed for
sonography include the real-time visualization of applicator placement,
portability of the technology, nearly universal availability, low cost, and
ability to target and guide ablation therapy with intracavitary endoluminal
transducers (i.e., for transrectal or transgastric energy application to the
prostate and abdominal organs). Limitations of sonography include occasional
poor lesion visualization as a result of a lack of innate tissue conspicuity
or overlying bone- or gas-containing structures. MR imaging generally provides
greatest tumor-to-tissue conspicuity and the ability to use multiplanar
guidance. However, this technology is relatively expensive, requires
specialized ablation equipment that is compatible with a high magnetic field,
and is the least available for general clinical use. CT and, more recently,
real-time CT fluoroscopy have also been used to ensure adequate positioning of
the energy applicator. Though CT fluoroscopy has not been extensively
evaluated, it is fair to say that CT falls between sonography and MR imaging
with respect to cost, tissue contrast, and complexity. In our clinical
practice, we use a combined approach of CT fluoroscopy and sonography at the
same setting to document optimal RF electrode positioning
(Fig. 3B).
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Diagnostic Imaging to Guide Therapy
To prevent under- or overtreatment of a lesion, it is essential to have
accurate and reliable methods for determining the adequacy of therapy. Thus,
significant investigation into the development of imaging strategies that
enable rapid assessment of the extent of tissue destruction induced by thermal
ablation is being conducted. Despite initial enthusiasm, gray-scale
sonographic findings observed during the thermal ablation procedure are not
sufficiently accurate in predicting the extent of coagulation
[7,
8,
53]. The progressively
increasing hyperechogenic focus often seen surrounding the distal portion of
the applicator during the application of energy represents microbubbles of gas
that form in the heated tissue and does not represent tissue coagulation
[54]
(Fig. 2B). This hyperechogenic
region can be variable in size, may be quite irregular in shape and contour,
and often shows complete resolution within 1 hr of ablation
(Fig. 2C). Additionally, this
intense echogenicity can often obscure the energy applicator and tumor while
increasing the difficulty of repositioning for further treatment.
Conventional color-flow and power Doppler sonography have similarly not been found useful in assessing the extent of induced coagulation [7, 8]. However, in one study contrast-enhanced color Doppler sonography with a synthetic microbubble sonographic contrast agent was able to achieve 92% accuracy in predicting the extent of coagulation in VX2 rabbit tumors immediately after RF ablation [55]. Additionally, sonographic contrast material has been used to direct a second energy application to residual enhancing (and presumably viable) foci within the treatment zone [56].
For solid organs such as the liver, unenhanced CT scans obtained immediately after ablation often reveal increased density at the center of the treatment zone, most often surrounded by a region of hypoattenuation [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 53, 57, 58]. With the exception of encapsulated lesions such as those of hepatocellular carcinoma, the margins of this outer hypodense zone are often too diffuse to be of sufficient sensitivity to assess therapy. However, contrast-enhanced CT is useful in discriminating between ablated and residual viable tumor immediately after thermal ablation because it shows regions of hypoattenuation devoid of characteristic tumorous or parenchymal enhancement in treated portions of the tumor. For intrahepatic metastases, the differentiation of coagulation necrosis from hypoattenuating tumor is usually easiest on images in the equilibrium phase of contrast enhancement (5-10 min after iodinated contrast administration). At this phase, persistent hypoattenuation is seen in coagulated tissues but not in viable tumor [31]. Hepatic arterial phase images are most useful for early-enhancing hepatocellular carcinomas (Fig. 3A, 3B, 3C, 3D). Imaging during the hepatic arterial phase can also show a thin rim of contrast material corresponding on histopathology to an early inflammatory reaction to the thermal damage (Fig. 3C). This inflammatory rim can be seen immediately after ablation and often regresses during the first month after treatment.
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MR images characteristically reveal altered signal on both T1- and T2-weighted images [53, 57, 59] (Fig. 4A, 4B, 4C, 4D). Treated areas are devoid of gadolinium enhancement. Several studies have documented the particular usefulness of decreased signal on T2-weighted images as a marker for induced coagulation [59, 60]. Radiologic—pathologic correlation in both experimental and clinical studies has shown that CT and MR imaging findings predict the region of coagulation to within 2-3 mm [31].
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One key advantage of MR imaging over other diagnostic imaging techniques is its ability to aid in determining the extent of coagulation during energy application. Heat-sensitive sequences have been constructed and permit tailoring of energy deposition [61, 62, 63]. Such a strategy is most useful in allowing the operator to limit energy deposition when heating adjacent to a critical structure (i.e., nerves) reaches cytotoxic temperatures. Pulsing switches were developed to overcome interference of RF and microwave usage during the acquisition of MR-RF encoded data [64].
Long-Term Imaging Follow-Up
Although initial imaging can serve as a good indication of the adequacy of
therapy, the resolution and accuracy of current imaging techniques preclude
identification of residual microscopic foci of malignancy, particularly at the
periphery of a treated lesion (where blood flow is greatest). These viable
tumor foci will inevitable continue to grow and, if untreated, will result in
failed therapy. Additionally, considering issues of sampling error and the
possible difficulty in differentiating between adequately treated and viable
tumors with histopathologic techniques alone, we have not found the use of
needle biopsy helpful. Thus, longterm imaging follow-up is necessary to find
untreated regions of the tumor or to document complete treatment of a given
focal malignancy.
Long-term follow-up of thermal ablation with sonography has limited value [7, 8]. Obscuration of the characteristic peritumoral halo observed before treatment is often seen, and the variability of gray-scale sonographic changes precludes accurate assessment of induced coagulation. Sonographic microbubble blood pool agents such as SH 508 A (Levovist; Schering, Berlin, Germany) may be helpful in differentiating treated tumor from the avascular coagulation at 6 months of follow-up [65].
Contrast-enhanced CT has been the mainstay of long-term imaging follow-up (Figs. 3A, 3B, 3C, 3D and 5A, 5B). Coagulated nonenhancing regions increase in conspicuity and develop sharper margins by 2 weeks after ablation [31, 53]. Imaging at 6-12 months can show marked regression of the lesion and the region of induced coagulation necrosis. Most commonly, the nonenhancing treatment focus shrinks less than 20% in volume. A peripheral rim that densely enhances on delayed contrast images often surrounds the region of coagulation. This finding should not be misconstrued as residual tumor, for experimental and clinical studies have shown this rim to represent an inflammatory reaction to the thermally damaged cells [53, 66]. A bulky irregular rim at the edge of a treatment site is the most common appearance of an incompletely treated lesion (Fig. 6).
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When using MR imaging for long-term follow-up (>3 months), we have relied primarily on the presence or absence of gadolinium enhancement in the treated region [8, 53]. In comparison with MR images obtained within 3 days of ablation, we have observed heterogeneous alteration on unenhanced T1- and T2-weighted images (4A, 4B, 4C, 4D). This changing variability in signal intensity throughout the ablated region is most likely caused by an uneven evolution of the necrotic area and the host response to thermal damage. Hence, these images have been thus far too variable to be relied on as adequate proof of tumor destruction. The multiplicity of potential imaging sequences and parameters used for MR imaging has only further compounded this problem. Further research may ultimately lead to greater insight into the biologic mechanisms that account for such signal heterogeneity. For gadolinium-enhanced images, it is also common to detect a thin rim of enhancement after treatment. As for CT scans, only when this rim appears bulky is this finding to be interpreted as representing an untreated tumor.
Nuclear medicine has been used in a limited number of patients after ablation therapy. In one study, positron emission tomography scanning with a radioactive glucose analog (18F-fluorodeoxyglucose) was used to detect active foci of residual tumor after percutaneous ethanol instillation in intrahepatic metastases [67].
Our current imaging strategy after thermal ablation includes an initial contrast-enhanced CT or MR study on the day of treatment to determine whether the patient has residual gross viable disease that requires immediate retreatment. Follow-up imaging is then performed at 1 and 3 months, and every 3-4 months thereafter. These scans are helpful in documenting the presence or absence of residual tumor that often may be amenable to additional thermal ablation treatment. If no evidence of peripheral tumor regrowth is seen by 6-12 months, adequate treatment can be inferred.
Trends for Thermal Ablation Therapy
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TopIntroductionInduction of Coagulation...Sources of Thermal EnergyHeat-Tissue InteractionsSources of Heat LossDiagnostic Imaging for Thermal...Trends for Thermal Ablation...ConclusionReferences |
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Presently, many thermal ablation devices are being studied with multiple commercial devices now becoming available. Given the rapid pace of evolution in the state of the art for ablation technologies, we cannot confidently predict which method (if any) will prove dominant for any given clinical application. Competitive technologies must be able to ablate the desired volume of tissue in a reproducible and predictable fashion. However, other factors, including ease of clinical use and cost, will play a role in determining which of these technologies will receive the greatest attention.
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TopIntroductionInduction of Coagulation...Sources of Thermal EnergyHeat-Tissue InteractionsSources of Heat LossDiagnostic Imaging for Thermal...Trends for Thermal Ablation...ConclusionReferences |
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TopIntroductionInduction of Coagulation...Sources of Thermal EnergyHeat-Tissue InteractionsSources of Heat LossDiagnostic Imaging for Thermal...Trends for Thermal Ablation...ConclusionReferences |
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