Percutaneous Radiofrequency Ablation of Liver Tumors

Anatomy and Physiology

The liver has a dual blood supply. The portal vein, which is responsible for splenic and intestinal drainage, provides approximately 80% of the blood supply to the liver. The portal vein forms by the union of the splenic vein and the superior mesenteric vein. The inferior mesenteric vein drains into the splenic vein. The hepatic artery supplies the remaining 20%. In most people, the proper hepatic artery branches from the common hepatic artery, which originates at the celiac axis. The proper hepatic artery subdivides into the right and left hepatic arteries, which provide flow to the right and left hepatic lobes, respectively. However, multiple anatomic variations of the right and left hepatic arteries exist; these variants are known as "accessory" or "replaced" vessels. The right hepatic artery is considered accessory or replaced when it originates from the proximal aspect of the superior mesenteric artery, while the left gastric artery is often the origin of an accessory or replaced left hepatic artery.[3]

Three hepatic veins allow for drainage of the liver. The liver is divided into anterior and posterior segments by the right hepatic vein. The left hepatic vein separates the liver into medial and lateral segments. The middle hepatic vein lies in the same plane as the inferior vena cava and the gallbladder fossa; it partitions the liver into the right and left lobes. The portal vein does not provide venous hepatic drainage, but it does divide the organ into the upper and lower hepatic segments.[3]

There are multiple classification schemes for describing the various portions of the liver; the Couinaud system is the most widely used. According to Couinaud, the liver is divided into eight independent functional sections. Each section has its own portal pedicle comprised of a branch of the right or left hepatic artery, a branch of the portal vein, a hepatic venous branch, and a bile duct. The sections are numbered in a clockwise manner. The caudate lobe is segment I. Segment II is the anterior segment of the left lobe, and segment III is the posterior segment of the left lobe. The medial segment of the left lobe is segment IV. Together, segments II, III, and IV represent the left lobe of the liver. Conversely, the right lobe is comprised of segments V and VIII anteriorly and segments VI and VII posteriorly. Classification of these various segments of liver anatomy is important to both radiologists and surgeons alike, especially for preprocedural localization of focal hepatic lesions.[3]

Indications

Hepatocellular carcinoma at a very early or early stage ("very early" stage includes patients with Child-Pugh A liver function and an Eastern Cooperative Oncology Group performance status of 0; early" stage includes patients with Child-Pugh A-B liver function and an Eastern Cooperative Oncology Group performance status of 0).[4][5] 

• Liver metastases (traditionally, metastases from a colorectal primary but now also indicated for metastases from breast, thyroid, and neuroendocrine primaries.[6][7][8] 
• Hepatoma awaiting liver transplantation[9]
• The primary treatment for small tumors (a single tumor measuring 5 cm or less in diameter; 3 or fewer tumors, each measuring 3 cm or less in diameter)[10][11][12]
• Inoperable tumors (whether due to intrinsic characteristics of the lesion(s), the inability of the patient to tolerate general anesthesia or advanced age/comorbidity), recurrent tumors, or progressive tumors.[13][14]

Contraindications

Absolute Contraindications

• Surgically resectable tumors and/or favorable transplantation status (if the tumors are deemed operable and/or the patient is a good candidate for transplantation, these methods of treatments should be pursued as they currently provide the best outcomes)[1]
• Vascular invasion by the tumor(s)[15]
• Tumor location of less than 1 cm from the main biliary duct (at this distance, bile ducts are at risk of injury when not protected simultaneously with intraductal cooling. Abscess formation, biliary stenosis, and biliary obstruction occur more frequently when bile ducts are within the area of thermally induced necrosis)[15]
• Intrahepatic biliary tree dilatation[15]
• Exophytic tumor location (due to the risk of tumor seeding)[15]
• Uncorrectable coagulopathy[15]

Relative Contraindications

• Extrahepatic metastases (treatment of liver tumors may be attempted if successful treatment of extrahepatic metastasis is felt to be achievable)[16]
• Bilioenteric anastomosis (due to potential infection; antibiotic prophylaxis may aid in prevention)[17]
• Superficial/subcapsular lesions, especially adjacent to any portion of the gastrointestinal tract or gallbladder (risk of thermal injury of the gastric/bowel wall or iatrogenic cholecystitis; open approach preferred)[18]
• Child-Pugh class C cirrhosis or decompensated liver disease[4][5]
• Tumors difficult to reach with electrodes or when electrode placement is impaired (In these cases, an open approach is preferred)[19][20]
• Single tumor greater than 5 cm in diameter or multiple lesions each greater than 3 cm in diameter (RFA may be utilized in larger hepatic tumors with the purpose of debulking the lesion prior to chemotherapy or for pain relief as opposed to definitive treatment)[10][11][12]
• More than 3 tumors (treatment of more lesions may be attempted if successful treatment is felt to be achievable)[10][11][12]
• Tumors immediately adjacent to hepatic vasculature (flowing blood usually protects the vascular wall from thermal injury but decreases procedure efficacy due to heat loss by convection)[18]

Equipment

RFA is an ablation technique that creates areas of tissue necrosis by applying heat to cancerous tissues. To create the zone of ablation, alternating current is applied to the tumor via an electrode. To create a closed electrical circuit, the electrode operates as a cathode, while multiple grounding pads attached to the skin behave as an anode. Ions in close proximity to the electrode reverberate quickly while attempting to line up with the alternating current. This results in elevated temperatures within both the tumor (direct heating) as well as the surrounding tissues (indirect heating) - the combination of these effects comprise the final zone of ablation.[21][22]

RFA requires 3 main pieces of equipment:[23]

• A probe (electrode needle with deployable ablative tynes and thermocouples)
• An electrical generator
• Multiple grounding pads

There are two forms of needle electrodes. A straight, solid needle is the first type. The second type is more complex - the needle is straight but hollow, containing multiple curved tynes that are retracted until the needle tip is placed inside a lesion. Incorporated into the tips of the tynes are thermocouples which act as tiny thermometers, allowing for continuous temperature monitoring throughout the procedure. Once appropriately situated in the tumor, the electrode tynes are advanced. The extended tynes resemble the spokes of an open umbrella.[23]

The RF generator is coupled to the electrode through insulated wires as well as multiple grounding pads, which are positioned on the skin of the thighs of the patient. The electrical generator creates an alternating current of approximately 300-500kHz (the RF range).[23]

Preparation

Preprocedural Imaging, Laboratory Analysis, and Consent

Patients should only be deemed appropriate candidates following the evaluation of their specific case either via multidisciplinary tumor board or in conjunction with surgical and oncology services, as resection still represents the best curative option for good surgical candidates with appropriate hepatic reserve. Patients that are deemed appropriate for RF require an imaging workup prior to the procedure. This typically includes a contrast-enhanced computed tomography (CT) and/or gadolinium-enhanced magnetic resonance imaging (MRI) for both tumor staging and planning of RFA needle trajectory.[24]

Laboratory evaluation is performed on all patients. Tests typically include coagulation studies, liver function studies, and tumor marker levels. A histological tissue sample confirming the diagnosis (or pathognomonic image findings with high levels of concordant tumor markers) is required for patients with hepatocellular carcinoma.[24]

Finally, patients deemed candidates for percutaneous hepatic RFA must meet with the physician, typically an interventional radiologist, who will be performing the procedure to discuss risks, benefits, and alternatives to the procedure. Patient questions are answered at that time.[24]

Anesthesia

Percutaneous RFA is typically performed under general anesthesia, although the use of local anesthesia and mild/deep sedation have been described in the literature. The type of anesthesia will play a role in determining if the procedure is performed as an outpatient, same day, or overnight stay. General anesthesia is usually preferred by most interventionalists as it allows patients to better tolerate any discomfort associated with the procedure. Interestingly, at least one study demonstrated a reduction in tumor recurrence in patients who underwent percutaneous RFA for small hepatocellular carcinomas under general anesthesia.[25]

Positioning

Positioning depends entirely on the imaging modality utilized for the procedure, the location of the tumor(s), the type of anesthesia, and physician/patient preferences. The goal is to avoid compromising the ability of the interventionalist to see and treat the tumor satisfactorily.[24]

Technique or Treatment

Procedure

Percutaneous RFA is performed by an interventional radiologist in the radiology suite after anesthesia/sedation.[18]

Before a needle is inserted into a lesion, the point of entry, a safe trajectory, and the end position of the needle are planned via a review of pre-procedural imaging. Once a window of access is determined, the probe is introduced to the tumor percutaneously, typically under sonographic or computed tomographic (CT) guidance. Then, if required, a local anesthetic may be administered along the tract. Subsequently, the electrode is advanced through the anesthetized track and into the mass.[18]

RFA is performed in the same manner despite the probe type; the only variations are the amount of power utilized and the length of ablative time. For lesions equal to or less than 2 cm in diameter, a needle electrode is positioned centrally within the tumor. The electrode tynes are extended to deliver 50 to 200 watts of alternating current. Once the temperature reaches 90°C, ablation is performed for approximately 8 to 25 minutes. The duration of ablation depends on the type of probe utilized. Both the tumor and a 1 cm surrounding margin of normal tissue are ablated. A tyne temperature of at least 60°C, approximately 30 seconds after the ablation ends, is necessary to ensure satisfactory tumor necrosis.[18]

Large tumors require multiple overlapping ablation fields. Instead of placing the probe at the center of the lesion as is done with smaller lesions, the electrode is positioned along the distal edge of the tumor. Several superimposed ablations are performed sequentially, moving proximally until the entire lesion and a 1 cm margin of normal tissue have been adequately ablated. Successful RFA requires sustained progressive heat. This ensures that the temperature required to cause coagulative necrosis is reached without creating "charring" (carbonization), which can hinder electrical flow and, thus, tissue ablation.[18]

After the ablation, the electrode is withdrawn while cauterizing the entry tract in an effort to prevent seeding of the pathway by tumor cells. For tumors located near vasculature, heat may be dissipated by cooler blood flowing through these vessels - an effect known as "heat sink." To attain effective temperatures in these cases, the tynes must be rotated or withdrawn slightly.[18]

Postoperatively, patients undergo immediate repeat imaging (typically with contrast-enhanced CT) to evaluate the ablation(s) and look for potential complications.[18]

Post-Procedural Assessment and Follow-Up

RFA is typically performed in specialty centers. This allows for evaluation by radiologists familiar with the post-RFA image appearance of treated (and recurrent) tumors. Post-RFA assessment often involves CT, ultrasound, MRI, and/or PET imaging. Studies are typically performed 4 to 6 weeks following the ablation. Later follow-up imaging studies may occur on a variable schedule but should be aimed at detecting local tumor recurrence, development of new lesions, or the emergence of extrahepatic disease.[15]

Contrast-enhanced CT

Perihepatic fluid, right lung base pulmonary consolidation, and right-sided pleural effusion are normal, commonly seen changes on immediate post-RFA imaging. Free fluid in the peritoneal cavity can also be seen, which typically resolves in days.[7] Iatrogenic arterioportal shunting and small peri-tumoral foci of air as well as RFA-induced arterioportal vascular shunting are also frequently seen on immediate post-procedural CT and frequently resolve within one month.[26]

A smooth, uniform, symmetric, concentric rim of enhancement surrounding the ablation zone, which represents a benign physiologic response to thermal injury, is the most common imaging feature in the first month.[27] Nearly 90% of patients will have this finding.[28]

A low-density lesion with no contrast enhancement approximately 1 to 3 months following the procedure represents a successful ablation.[27] The shape of the lesion is not considered a significant parameter to differentiate between treatment success or failure.[29] Conversely, thick, nodular, eccentric rim enhancement and/or an increase in the size of the treated lesion are reliable indicators of tumor recurrence and, thus, treatment failure.[30]

Four different contrast-enhanced CT recurrence patterns following RFA have been described in the literature:[31]

• Ingrowth: Enhancing tissue inside the border of the treated lesion, denoting inward growth of the tumor.
• Outgrowth: Enhancing tissue expanding outward from (but contiguous with) the border of the treated lesion, denoting outward growth of the tumor.
• Spread: New enhancing tissue separate from the treated lesion but contained within the same Couinaud liver segment
• Progression: New enhancing tissue seen in different Couinaud liver segments from the treated lesion

The post-ablation zone of necrosis should be larger in size than the actual lesion due to the additional 1 cm margin of normal hepatic parenchyma included in the ablation. If an ablation zone is noted to incompletely encompass the original lesion, close follow up is advised as viable tumor cells may still be present.[26] The ablation zone may remain the same size or gradually decrease over time. Calcification may or may not develop along the edge of the ablation zone.[7]

Ultrasonography

Grayscale

Sonographic exam following RFA will be variable. A simple grayscale sonographic exam in and of itself is not a sensitive imaging modality for follow-up due to limited ability to differentiate between an area of RFA-induced necrosis and residual tumor. Ultrasound findings post RFA are variable and may show echo-poor, echogenic, or mixed appearance.[26]

Contrast-enhanced

While not readily available at all institutions, contrast-enhanced sonography represents a rapid and cost-effective alternative to traditional CT and MRI post-RFA follow-up imaging studies. Additionally, ultrasound examination inherently lacks the radiation exposure of the aforementioned traditional follow-up modalities.[32]

Interestingly, multiple sources report that RFA-induced changes, such as necrosis, often appear smaller when imaged with contrast-enhanced ultrasound versus contrast-enhanced CT.[33]

Limitations of contrast-enhanced ultrasound include limited ability to visualize the safety margin (the additional 1cm of ablated normal parenchyma surrounding the tumor).[7]

Magnetic Resonance Imaging

MRI with or without gadolinium may be useful for assessing outcomes after RFA. A contrast-enhanced study will inherently be more useful than a plain, unenhanced one due to improved visualization of the ablation zone.[34]

On MRI, ablation should be considered a success if there is no residual tumoral enhancement as well as low signal intensity on T2-weighted images.[35]

While more time consuming than CT, MRI is more sensitive than CT at detecting tumor regrowth. Local tumor recurrence is often seen on T2-weighted images earlier than on contrast-enhanced CT.[33]

Complications

Post-ablation Syndrome

Post ablation syndrome is a common, self-limiting phenomenon observed in nearly one-third of patients following RFA. The symptoms are flu-like, last approximately seven to ten days following the procedure, and include the following:[36]

• Low-grade fever
• Delayed pain
• Malaise
• Myalgia
• Nausea
• Vomiting

Hemorrhage

Hemorrhage, both intra-abdominal and intra-hepatic, is the most frequent post-RFA complication seen,, according to numerous studies. Bleeding typically occurs due to direct trauma from improper positioning of the electrode with resultant injury to small vessels as opposed to direct heat-related injury. It may be venous or arterial in nature and commonly presents as increasing abdominal pain after RFA. Imaging such as CT or ultrasound is confirmatory. Hemorrhagic complications occur more often in patients with hepatocellular carcinoma due to coagulation issues related to underlying cirrhosis. This complication can be preempted by avoiding hepatic vessels during the positioning of the electrode whenever possible, highlighting the essential role of effective imaging guidance. Venous hemorrhage usually ceases spontaneously without additional intervention and/or blood transfusions only; arterial bleeding may be more severe, requiring endovascular or, more rarely, surgical intervention. Cauterization of the needle tract on the removal of the electrode probe should always be performed to help reduce this complication.[37]

Hemothorax may also occur but less frequently than abdominal hemorrhage. Thoracic hemorrhage usually results from arterial injury while performing RFA for lesions in the right hepatic lobe utilizing an intercostal approach. The most common symptoms are shortness of breath and chest pain. Ultrasound, CT of the chest, and/or chest X-ray are confirmatory. Invention to aid in the cessation of hemorrhage, as well as drainage, are typically necessary.[37]

Hemobilia, bleeding within the bile ducts, is another type of RFA-related hemorrhage. It occurs when both a bile duct and a hepatic artery/vein are simultaneously punctured. Abdominal pain is the most common symptom, albeit nonspecific. The biggest issue with hemobilia is the resultant obstruction of the biliary tree with thrombus, which can result in biliary dysfunction and, thus, jaundice and hepatic failure. Tumors in the caudate lobe (Couinaud segment I) pose the highest risk for this complication. Avoidance of dilated biliary radicles during the placement of the electrode probe should aid in prevention.[37]

Bleeding within the liver capsule, known as a subcapsular hematoma, as well as bleeding within the abdominal wall have also been described. A subcapsular hematoma usually occurs when performing RFA on tumors located immediately below the liver's surface. This location is prone to this complication because the electrode tract cannot be cauterized on withdrawal due to its shallow depth.[37]

Infection

Infection is another relatively common entity encountered following an RFA procedure. The category of RFA-associated infection is broad and includes abscess and wound infection. Post-RFA abscess is an insidious complication as it can appear long after the procedure. Risk factors for the development of post-RFA abscess include anomalous biliary anatomy (Whipple or other forms of bilio-enteric anastomosis, prior papillotomy, etc.), which render a patient susceptible to ascending infection. The most common symptoms of liver abscess are fever and abdominal pain. The signs and symptoms of hepatic abscess typically occur in less than four weeks following RFA but can occur as far out as 60+ days. While a fever immediately following RFA is common and may be related to post-ablation syndrome, a fever that persists beyond two weeks should raise suspicion for an infectious etiology. CT scan is confirmatory. Enterococcus, Escherichia, Bacteroides, Clostridium, and Klebsiella are the most common culprits. Treatment requires a combination of both antibiotic therapy and percutaneous drainage.[37]

Biliary Tract Damage

Damage to the biliary tract encompasses direct ductal injury, stricture, biloma, and, far more rarely, bilioperitoneum and bilio-pleural fistula/bilious effusion. Biliary tract damage is the result of direct thermal injury from RFA as well as electrode-mediated mechanical injury. These types of complications are most common in tumors located in the hepatic hila or in lesions within 1 cm of major bile ducts. Such close proximity to these ducts impedes the safe procurement of the necessary margin of normal hepatic parenchyma surrounding the tumor. Of the aforementioned complications, biliary strictures are the most common. A stricture of the biliary tract can develop anywhere from one week to several months following RFA. The diagnosis is typically made via CT or MRCP. ERCP represents both a diagnostic and therapeutic modality as it may be used for stent placement if the stricture is located in the hilum or common bile duct. Strictures at the level of the ampulla of Vater are treated via endoscopic sphincterotomy.[37]

Biloma, an organized collection of bile located outside of the biliary tree, results from damage to the biliary tract and subsequent leakage of bile. Bile duct injury resulting in biloma may be mediated by direct mechanical injury from the electrode probe as well as thermal damage. When seen with CT, it appears as a well-circumscribed fluid collection generally in close proximity to the ablation zone. The majority of bilomas occur within the first four months following RFA but have been reported as far out as 17 months in the literature. Most patients experience no symptoms, and in about 50% of cases, the biloma regresses without intervention. Percutaneous drainage is required for resolution in the other half of patients. Focused imaging evaluation of the sphincter of Oddi is important to exclude increased biliary pressure related to RFA-induced biliary stenosis as an occult etiology for biloma formation.[37]

Liver Failure

Liver failure is one of the most severe RFA-related complications as it can be fatal in patients with hepatic cirrhosis whose liver function is typically already impaired. Prior partial hepatectomy is another risk factor as these patients lack the parenchymal volume to mount an effective compensatory functional response. The acute (or acute on chronic) failure is thought to occur due to vascular injury, which results in hepatic infarction. Preprocedural imaging with careful electrode entry point planning is essential to avoid this complication. Another suggested cause of post-RFA liver failure is overly extensive ablation in the setting of cirrhosis. The destruction of impaired but functioning parenchyma may push the patient into overt liver failure.[37]

Pulmonary Complications

Pneumothoraces, pleural effusions, and cases of pneumonia are examples of RFA-related pulmonary complications. As one might expect, pneumothorax is commonly associated with the treatment of hepatic lesions in close proximity to the diaphragm, for which an intercostal approach is necessary. Satisfactory electrode probe positioning in a safe window predetermined by preprocedural imaging reduces the risk. CT evaluation is required with dyspnea or chest pain are experienced by the patient following RFA. If present, admission to the hospital and vital sign monitoring may be warranted. For large, quickly enlarging, or symptomatic pneumothoraces, chest tube placement with serial chest x-rays is usually necessary.[37]

Cutaneous Thermal Injury 

Skin burns are a known complication related to RFA. They typically occur at two sites: the point of electrode probe entry and along the grounding pads. Life-threatening scorch injuries are rare but have been reported in the literature. Manufacturer increases in the number and size of the grounding pads have, in recent years, greatly reduced the occurrence of this complication because larger and more numerous pads more effectively disperse the high volume of energy generated by the electrical current. Additionally, satisfactory pad placement with adequate skin contact and equidistant positioning from the electrode probe is also essential in the prevention of skin burns. Asymmetric distribution of electrical current may occur when the pads are not appropriately positioned, which prevents temperature uniformity and, thus, higher temperatures in the pads closer to the probe, resulting in cutaneous damage.[37]

Tract Seeding

The seeding of the electrode probe tract is a well-described phenomenon associated with percutaneous RFA. Transfer of tumor cells from the lesion to the probe tract occurs when viable cancer cells adhere to the probe on withdrawal following the procedure. Choosing the entry point with the least amount of hepatic parenchyma between the skin and the lesion, as well as decreasing the number of probe punctures, helps to decrease the frequency of this complication. Optimum, first-attempt probe positioning should be the goal. Furthermore, cauterization of the probe tract has also effectively lowered the rate of occurrence. Additional factors that place a patient at risk for developing tract seeding include cancer, which is poorly differentiated, subcapsular tumor location (a contraindication to tract cauterization), and multiple electrode probe insertions.[37]

Hepatic Vascular Damage

With hemorrhage having been described above, remaining RFA-related vascular complications include thrombosis of the portal vein and/or hepatic vein as well as pseudoaneurysm formation. Coagulation with resultant thrombosis of vasculature in excess of 3 mm is rare when normal anatomical blood flow is present. Because of extensive collateralization of both arterial and venous blood supply to the liver, most thromboses are asymptomatic such that no intervention is necessary. Blood clots are the result of thermal endothelial damage, which leads to the aggregation of platelets and subsequent activation of the coagulation cascade. Care should be taken to avoid this complication, particularly in patients with cirrhosis, because it could push a patient with preexisting liver dysfunction in fulminant liver failure. In this setting, portal vein thrombosis represents a potentially life-threatening complication. [37]

RFA-induced thermal damage to the hepatic artery may result in small-scale arterioportal shunting. The majority of these small defects will heal spontaneously. In the absence of self resolution, these shunts can be corrected with endovascular intervention.[37]

Visceral Damage

While extremely rare, RFA-related damage to the abdominal organs has been reported in the literature. Peripherally located and subcapsular tumors (less than 1 cm from nearby organs) impart the highest risk. Additional factors that increase the risk of abdominal organ injury include prior abdominal surgery as well as chronic cholecystitis (which is known to cause adhesions between the liver and bowel). In these cases, an open or laparoscopic RFA approach is preferred to confirm these organs are physically separated. Hydrodissection (also known as artificial ascites) may help mitigate the risk. This technique involves the introduction of 5% dextrose or normal saline to the peritoneal cavity in order to increase the distance between the liver and abdominal viscera.[37]

Clinical Significance

In addition to percutaneous radiofrequency ablation, several additional ablative techniques such as microwave and cryotherapy have emerged as effective alternatives. According to the literature, the overall survival and local recurrence rates, as well as complications and mortality rates in liver metastases patients treated with radiofrequency ablation (vs. microwave ablation), are not statistically different in terms of both survival time from diagnosis and survival time from ablation.[38]

Enhancing Healthcare Team Outcomes

Percutaneous local treatment is an attractive new tool for patients with cancer, especially for disease in the liver. There is no effective treatment currently available for the vast majority of patients with metastatic liver disease. Most primary liver tumors are unresectable at diagnosis. In such cases, local treatment preserves uninvolved liver tissue and has potentially fewer systemic complications. It has less morbidity and mortality in comparison to major liver surgery as well. However, it is not a replacement for surgery.

An interprofessional team approach is vital to the care of the oncology patient. Interventional radiologists work closely with surgeons, oncologists, radiation oncologists, and other specialists with the goal of providing the best possible outcome for these patients.