Digestive Disease Interventions 2024; 08(02): 130-136
DOI: 10.1055/s-0044-1782149
Review Article

Interventional Radiology Management of Pediatric Liver Tumors

Tammy Kim
1   Department of Radiology, Boston Children's Hospital, Boston, Massachusetts
,
1   Department of Radiology, Boston Children's Hospital, Boston, Massachusetts
› Author Affiliations
 

Abstract

Pediatric liver tumors are not only rare, they are also different from the adult liver tumors. Hepatoblastomas and hepatocellular carcinomas (HCCs) are the most common primary malignant tumors seen in children. Fibrolamellar HCC, sarcomas, cholangiocarcinoma, germ cell tumor, and rhabdoid tumor and metastatic tumors comprise the remainder of liver malignancies. Hepatic infantile hemangiomas, mesenchymal hamartoma, regenerative nodules, adenomas, and focal nodular hyperplasia are the common benign liver tumors of childhood. The Pediatric Hepatic International Tumour Trial (PHITT) is an international trial with the goal of evaluating new and existing treatments for pediatric liver tumors. Chemotherapy, surgery, and liver transplantation are well-established in the management of pediatric liver tumors. In the background of increasing incidence of pediatric tumors, and availability of newer, less invasive modalities to treat tumors, it is vital to understand the role of interventional radiology in the management of pediatric liver tumors.


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Malignant liver tumors in the pediatric population are rare, making up only 0.5 to 1.5% of all pediatric cancers.[1] [2] In contrast to liver tumors in adults, two-thirds of all liver tumors in pediatric patients are malignant.[3] Hepatoblastoma and hepatocellular carcinoma (HCC) make up the vast majority of liver malignancies. Hepatoblastoma, the most common pediatric liver malignancy, is more prevalent in patients under the age of 5. Beckwith–Wiedemann syndrome, familial adenomatous polyposis, and extreme prematurity are risk factors for hepatoblastoma. Current multidisciplinary treatments, which include chemotherapy, surgery, and liver transplantation, have raised survival rate of hepatoblastoma to nearly 80%.[4] Hepatoblastoma patients are evaluated based on imaging findings to determine treatment according to the PRETEXT (PRETreatment EXTent of disease) criteria, as proposed by the Société international d'Oncologie Pédiatrique Epithelial Liver group (SIOPEL).

HCC represents the second most common hepatic malignancy and is seen more frequently in older (second decade) children, making up 25% of hepatic tumors.[5] Pediatric cases of HCC are distinct from their adult counterparts, as nearly 70% of cases in the Western world occur in patients with otherwise normal livers. Only 30% of pediatric HCC patients have underlying conditions such as biliary atresia, glycogen storage disease, viral hepatitis, or α-1-antitrypsin deficiency. In pediatric HCC patients, both the PRETEXT and TNM system are used to determine treatment. Management of pediatric HCC continues to be challenging and needs careful multidisciplinary planning. Complete resection of HCC in noncirrhotic liver without metastasis has a 5-year event-free survival of 70 to 88%.[6] In contrast to adults, nearly 50% of tumors in this population are chemotherapy-sensitive, which, however, does not translate to resectability.[7] In children with HCC, overall 5-year survival rate is less than 30%, as compared with less than 10% in adults with HCC.[8] [9] Other pediatric hepatic malignancies include hepatocellular malignant neoplasm not otherwise specified (which combines the histological features of hepatoblastoma and HCC), fibrolamellar HCC, sarcomas (e.g., undifferentiated embryonal sarcoma, biliary rhabdomyosarcoma, and angiosarcomas), cholangiocarcinoma, germ cell tumor, and rhabdoid tumor and metastatic tumors (neuroblastoma, Wilms tumor), comprise the remainder of liver malignancies. Fibrolamellar HCC, a variant seen in adolescents and young adults without underlying liver disease, accounts for about a third of HCC patients younger than 20 years.[10] The common benign liver tumors encountered in clinical practice include hemangiomas (infantile and congenital), mesenchymal hamartoma, regenerative nodules, adenomas, and focal nodular hyperplasia.[11]

The Pediatric Hepatic International Tumour Trial (PHITT) is an international trial with the goal of evaluating new and existing treatments for pediatric liver tumors.[10] Interventional radiology treatments may benefit patients for whom treatment remains challenging with current established approaches. This article aims to describe the role of interventional radiology in the diagnosis, and potentially in the treatment of pediatric liver tumors.

Percutaneous Interventions

Biopsy

Interventional radiologists play a significant role in the diagnosis of liver malignancies through image-guided biopsies. One potential anticipated result of PHITT is the adoption of standardized biopsy practices, which are currently not in place. All patients evaluated in PHITT are required to undergo pre-treatment biopsy of the primary hepatic tumor. The exception to this is any patient with tumor rupture that may experience life-threatening hemodynamic bleeding with tissue sampling.[10] Contrast-enhanced cross-sectional imaging of the abdomen is currently a mainstay of workup and staging patients with liver malignancies, and review of imaging can help determine potential approaches for biopsy. This can also facilitate selection of a biopsy tract that includes a future area of resection.

There are many traditional methods of liver biopsy, some of which are suboptimal for the evaluation of liver tumors. Per PHITT biopsy guidelines, the type of biopsy is left to the discretion of the institution.[10] Transjugular liver biopsy is often considered for patients with ascites or increased risk of hemorrhage, though largely reserved for non-targeted liver biopsies. Surgical biopsy is more invasive compared with percutaneous needle biopsy, and primary tumor resection is rare prior to chemotherapy.

Image-guided needle biopsy of liver tumors is minimally invasive, allows for precise needle localization, and decreases the risk of injury to the liver and adjacent structures. Typically, this is performed with ultrasound guidance, which does not involve ionizing radiation. Ultrasound also allows for the use of color or power Doppler imaging so that adjacent vessels can be avoided. By using a coaxial guide needle (e.g., a 15-gauge coaxial guide needle for a 16-gauge biopsy device), the liver capsule may be traversed only once to obtain multiple samples. Under ultrasound guidance, the guide needle is advanced just proximal to the lesion. The biopsy device can then be advanced through the coaxial needle to obtain needle cores of the lesion. Once within the capsule, the guide and biopsy device can then be redirected and angled under imaging guidance to sample different areas of a lesion, as recommended by PHITT guidelines. Ideally, this would include enhancing portions seen on post-contrast cross-sectional imaging, or contrast-enhanced sonography ([Fig. 1]), as these are more likely to represent non-necrotic, viable tumor. Alternatively, areas of tumor that display restricted diffusion on diffusion-weighted magnetic resonance imaging implicate areas of higher cellularity and may provide more information.

Zoom Image
Fig. 1 An 11-month-old child with trisomy 21 who has two focal liver lesions. He has a pacemaker on the right upper quadrant abdominal wall (a) precluding optimal MRI or CT imaging of the lesion. Contrast ultrasound was performed which showed one lesion enhancing (b) and another non-enhancing and necrotic (c). The former was targeted for percutaneous biopsy (d).

PHITT recommends between seven and twelve core needle biopsy specimens, preferably 16-gauge cores with a length of 20 to 30 mm. Though not standard practice, PHITT also recommends the biopsy of normal liver parenchyma, ideally yielding two or more cores.

While there are no studies that evaluate targeted liver biopsies, there are some studies that examined non-targeted percutaneous image-guided liver biopsies. There was no uniform description or categorization of minor and major complications. Overall, complication rates were between 1 and 18%, though the highest complication rate was seen in liver biopsies without image guidance in infants less than 3 months of age. In a study of 513 patients who underwent liver biopsy, 7.4% experienced minor complications, the majority of which were hemorrhage that did not require treatment, and 1% experienced major complications as defined by this series.[12] [13] [14] [15] [16] [17]

The most common complication of liver biopsy is hemorrhage; precautionary measures may be taken to minimize the risk of bleeding. Each child should be evaluated for thrombocytopenia or coagulation abnormalities that may increase the risk for bleeding. The Society of Interventional Radiology Consensus Guidelines recommend platelets above 50,000 per microliter and an international normalized ratio less than 1.8.[18] In addition, tract embolization may be considered. This is performed with a hemostatic agent, most commonly gelatin foam either made into a slurry with saline or gelatin foam pledgets. It is imperative to know that, although rare, Gelfoam can provoke anaphylactic reaction.[19] While PHITT recommends the use of tract embolization, there are no prospective trials studying the effect of tract embolization in pediatric liver biopsies.


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Percutaneous Ablation

Percutaneous thermal ablation devices have been used for a wide variety of tumors in the adult population. The most common types include radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation. Current studies examine their use for HCC in adults, as there have not yet been prospective studies involving the pediatric population. While each method of percutaneous thermal ablation carries slightly different characteristics, each of these may be more challenging to use in smaller patients, especially more central lesions. RFA has been used to treat hepatoblastoma and liver metastases.[20] [21] In hepatoblastoma, it is crucial not to delay surgery after preoperative chemotherapy. However, due to limited donor availability, the chemotherapy and liver transplant surgery can be challenging to plan, unless a living donor liver transplantation is anticipated. In such scenarios, a combination of resection and local RFA might be such an alternative option. RFA also has a hepatic sparing effect, leaving more healthy liver tissue in place than with more extensive resection especially in patients with a small remaining liver lobe.[21] RFA has also shown efficacy in the treatment of hepatoblastoma metastases to the lung, liver, and bones.[22] For thermal ablation, the probes are advanced under image guidance. Ultrasound is predominantly used in children for guidance, and multidetector computed tomography (CT)/cone beam CT as sparingly as possible to reduce radiation. For MWA and RFA, monitoring of the ablation zone is challenging under ultrasound due to the production of gas, and CT is preferred for monitoring during treatment. Cryoablation creates an “ice ball” in the treated area that can be visualized on ultrasound or CT.

RFA induces coagulation necrosis at the probe tip by introducing thermal energy.[23] The total ablation zone is heavily influenced by the thermal conductivity of surrounding tissue or the presence of adjacent blood vessels. Charred tissue may decrease the spread of energy, while cirrhotic liver is known to facilitate energy transfer. Unfortunately, cirrhosis is less commonly seen in pediatric HCC cases. RFA has been shown to be effective for smaller liver tumors (i.e., <3 cm), due to these limitations and smaller ablation zone.[24] [25] [26]

MWA has gained favor more recently, as this method allows for larger ablation zones and faster treatment times. MWA probes deposit thermal energy farther from the probe, resulting in a larger ablation zone.[27] This also renders it less susceptible to the presence of adjacent blood vessels and is more effective in tissues with higher impedence.[28] MWA has been used effectively in children with unresectable hepatoblastoma in combination with transarterial chemoembolization.[29]

Cryoablation makes use of the Joules-Thomson effect, in which rapid decompression of Argon gas creates cytotoxic temperatures of −25 °C or less.[27] Cryoablation probes can create an ablation zone of nearly 5 cm in length, depending on probe type and freezing parameters. Multiple probes can be used to create a larger cumulative cytotoxic zone.[30] [31] Cryoablation typically entails two 10-minute cryoablation cycles with intervening thaw cycles. Cryoablation is less affected by the heat-sink phenomenon from adjacent vessels. It also creates a visible ice ball, which can be used for real-time monitoring of treatment zone. The rapid release of cytokines into systemic circulation during thaw cycles may cause a rare complication called “cryoshock,” which may result in hypotension, tachycardia, thrombocytopenia, and disseminated intravascular coagulation.[32] The author has used this modality to treat metastatic liver tumor.

Two other methods of ablation that are not as widespread include irreversible electroporation and high-intensity focused ultrasound (HIFU). Irreversible electroporation induces apoptosis from increasing membrane potential, which causes irreversible cell membrane permeability. Like cryoablation, this method is less affected by adjacent tissue type and heat sink.[33] HIFU is a completely noninvasive treatment method that uses focused ultrasound beams to cause necrosis. Magnetic resonance imaging is typically used for guidance. While a study showed that HIFU was comparable to RFA for treatment of small HCCs, known challenges include long treatment times, difficulty with patient positioning, inability to treat lesions with overlying osseous structures such as ribs, heat-sink effect, and movement of treatment area with respiration.[34] [35] HIFU has been used in combination with TAE for local control for hepatoblastoma.[36]

A feared complication of percutaneous procedures involving a liver tumor is seeding of the tumor along the biopsy tract. The frequency of this in pediatric populations is unknown, though it has been reported in both biopsies and RFAs of HCC in adults. One study demonstrated that cauterization of the tract decreased the number of viable tumor cells on a biopsy needle from 17.9 to 0%.[37] While this may be inevitable with biopsies due to lack of biopsy devices that can perform cautery, many of the percutaneous ablation methods have cauterization capabilities that can be considered.


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Endovascular Interventions

In adults, endovascular therapies are used to treat non-resectable HCC, or to bridge patients to resection or transplant.[38] This technique takes advantage of dual hepatic blood supply, as HCC is known to parasitize hepatic artery branches. Catheters are advanced into hepatic artery branches supplying tumors to deliver embolics, drugs, and/or radioisotopes to deprive tumors of blood supply and deliver therapeutic agents in the tumor, while preserving arterial and portal venous supply to normal liver. One of the major contraindications to transarterial embolization is poor liver function. These treatments have not yet been studied prospectively for pediatric liver malignancies. For all methods of embolization, transient elevation of liver function tests may occur.[4] Another known complication is “post-embolization syndrome,” after transarterial chemoembolization which usually is a self-limiting illness, which includes abdominal pain, nausea, low-grade fever, and malaise. Children have been known to experience post-embolization syndrome more frequently than adults. There have been reports that this could be ameliorated with single pre-procedure dose of methylprednisolone, as well as post-procedure pain management and antiemetics. Post-procedure monitoring of response is typically done with cross-sectional imaging, though α-fetoprotein levels may be a useful surrogate in pediatric patients.

Bland Embolization

In bland embolization, a catheter is directed into hepatic artery branches supplying a tumor and occluding them with an embolic agents. With current tools, subselective catheterization is possible for more precise delivery. There is a wide variety of embolic agents, including gelatin, polyvinyl alcohol (PVA), trisacryl gelatin microspheres. Gelatin is an absorbable agent that lasts approximately for 2 weeks, making it less suitable for tumor embolization. PVA particles can be spherical or irregular in shape. Microspheres have the advantage of more regular distribution and decreased chance of clumping. They are calibrated by size and can be selected based on the treatment site. While larger particles can cause insufficient ischemia, particles that are too small may cause biliary necrosis. For pediatric patients, size of the patient must be considered, and distal selective embolization generally requires 40- to 120-μm microparticles, followed by 100- to 300-μm microparticles in the absence of arteriovenous shunting. In liver, bland embolization has been used to treat hepatic adenomas, ruptured HCCs, hepatoblastomas (in preparation for surgery), focal nodular hyperplasia, metastases from gastrointestinal stromal tumor ([Fig. 2]), and vascular tumors such as hemangiomas.[39]

Zoom Image
Fig. 2 A 13-year-old man with metastatic gastrointestinal stromal tumor to the liver. Axial T1-weighted contrast-enhanced MRI image (a) demonstrating the two enhancing focal lesions in the left lobe of the liver. The larger lesion was less vascular and treated with radiofrequency ablation and the smaller lesion was treated with bland embolization to avoid injury to the stomach wall. Follow-up axial T1-weighted contrast-enhanced MRI image (b) demonstrating tumor necrosis with no contrast enhancement.

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Chemoembolization

Chemoembolization delivers a chemotherapeutic agent directly into tumor arterial supply. In adults, the chemotherapeutic is doxorubicin. In addition to doxorubicin, use of cisplatin and mitomycin has been described in pediatric patients. Historically, various agents such as ethiodized oil or microparticles have been used as carriers for the chemotherapy. Currently, drug-eluting beads (DEBs) are commonly used.[40] [41] Both transarterial bland embolization and chemoembolization have been shown to cause tumor necrosis, and the added benefit of additional chemotherapeutic agent is controversial.[42] [43] DEB transarterial chemoembolization has been shown to elicit complete response to tumors less than 5 cm, while somewhat less effective for larger tumors.[4]

While chemoembolization is now considered standard of care for HCC in the adult population, it has yet to be prospectively studied in the pediatric population. In adults with inoperable HCC, it has shown improved overall survival at 2 years. It has also been used to bridge patients to transplantation and to downstage patients so that they may be eligible for transplant.[44] Chemoembolization has been utilized as neoadjuvant or to treat non-resectable liver hepatoblastoma or HCC and has been proposed as a bridge therapy for liver transplantation ([Fig. 3]).[39]

To date, there have been feasibility studies to demonstrate that chemoembolization is possible in children with liver tumors. Due to the smaller number of pediatric patients who can be considered for chemoembolization, it has been studied in a few case series.[45] In larger case series on pediatric HCC patients, patients who were not surgical resection or transplant candidates, six of eight patients were downstaged and able to undergo transplant. In one case series of nine pediatric patients with liver malignancies (six hepatoblastoma and three HCC patients), who were unresponsive to chemotherapy and not surgical candidates, transarterial chemoembolization was performed. All patients had response to therapy, and five were able to undergo surgery.[46] While encouraging, further prospective trials are needed to support the use of chemoembolization in the pediatric population.

Zoom Image
Fig. 3 A 2-year-old child with hepatocellular carcinoma with rising α-fetoprotein (AFP) level, unresponsive to systemic chemotherapy. Coronal contrast-enhanced CT image (a) demonstrated a large heterogeneously enhancing tumor. Transarterial chemoembolization (TACE) (b) was performed as a bridge to liver transplantation. Coronal contrast-enhanced CT image (c) after two sessions of TACE demonstrated a large tumor necrosis with subsequent significant reduction of AFP.

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Radioembolization

The experience of transarterial radioembolization in treating pediatric liver tumors is limited.[39] In this procedure, yttrium-90 microspheres are directly injected into a tumor via its arterial supply to deliver β radiation to achieve local doses of up to 150 Gy, a dose too high to be safely delivered via external beam radiation. Yttrium-90 can be delivered as glass microspheres or resin. The glass microspheres carry more radiation per particle compared with resin (1.2 vs. 25 million spheres to reach 3 GBq). For radioembolization, unlike chemoembolization, tumoral blood flow is essential for the generation of reactive oxygen species, which in turn induces apoptosis.[47]

Another key difference between other types of transarterial embolization, radioembolization, is typically conducted in two sessions. The first session is used to perform a planning angiogram. In the first session, the hepatic arterial supply is mapped, so that treatment volumes can be determined. Also, technetium-99m macro-aggregated albumin microspheres serve as surrogate for the yttrium-90 microspheres to determine the degree of pulmonary shunting. Two to 4 mCi technetium-99m macro-aggregated albumin microspheres are injected to the planned treatment vessels. HCC is known to cause arteriovenous shunting, which can cause non-target embolization to the lungs. Planar or single-photon gamma camera images are obtained post-procedure to determine the degree of radioactivity in the lungs. Lung shunt fraction greater than 20% is a contraindication for radioembolization. Doses to the lung over 30 Gy per session or over 50 Gy cumulatively have been associated with radiation pneumonitis.[48]


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Portal Vein Embolization

Portal vein embolization has been utilized in the adult patients with primary or metastatic liver tumors prior to surgical resection of the lobe with these tumors, to achieve adequate volume and functional status of the contralateral lobe of the liver—future liver remnant (FLR). Embolization of the portal vein branches of the tumor-containing lobe of the liver leads to augmentation of pressure in the main and contralateral portal vein branches, in turn leading to hyperexpression of genes involved in liver regeneration and delivery of important growth factors to the FLR.[49] The total liver and FLR volumes are evaluated after the procedure using cross-sectional imaging. FLR/TLV ratio of at least 30% in patients with otherwise normal liver parenchyma and at least 40% in patients with cirrhotic liver or extensive chemotherapy is required for postresection survival.[50] Typically, the majority of remnant liver hypertrophy occurs in 2 to 4 weeks post-procedure, at which time repeat cross-sectional study can be obtained for comparison.[51] In adults, 25 to 60% increase in the FLR volume can be achieved in 4 weeks depending on the type of portal vein embolization method used, quality of the liver, and time interval between the embolization and follow-up imaging. Data in pediatric population are limited.[52]


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Conclusion

Interventional radiology plays a significant role in the diagnosis of liver malignancies in pediatric patients. Both percutaneous and endovascular treatments for liver tumors is considered standard care in adults, though many of these techniques have yet to be studied in children. More trials like PHITT are needed to validate treatment options for those ineligible for surgical treatment.


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Conflict of Interest

None declared.

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Address for correspondence

Raja Shaikh, MBBS, MD
Department of Radiology, Boston Children's Hospital
300 Longwood Avenue, Boston
MA 02115   

Publication History

Received: 30 December 2023

Accepted: 02 February 2024

Article published online:
14 March 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

  • References

  • 1 Aronson DC, Meyers RL. Malignant tumors of the liver in children. Semin Pediatr Surg 2016; 25 (05) 265-275
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Zoom Image
Fig. 1 An 11-month-old child with trisomy 21 who has two focal liver lesions. He has a pacemaker on the right upper quadrant abdominal wall (a) precluding optimal MRI or CT imaging of the lesion. Contrast ultrasound was performed which showed one lesion enhancing (b) and another non-enhancing and necrotic (c). The former was targeted for percutaneous biopsy (d).
Zoom Image
Fig. 2 A 13-year-old man with metastatic gastrointestinal stromal tumor to the liver. Axial T1-weighted contrast-enhanced MRI image (a) demonstrating the two enhancing focal lesions in the left lobe of the liver. The larger lesion was less vascular and treated with radiofrequency ablation and the smaller lesion was treated with bland embolization to avoid injury to the stomach wall. Follow-up axial T1-weighted contrast-enhanced MRI image (b) demonstrating tumor necrosis with no contrast enhancement.
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Fig. 3 A 2-year-old child with hepatocellular carcinoma with rising α-fetoprotein (AFP) level, unresponsive to systemic chemotherapy. Coronal contrast-enhanced CT image (a) demonstrated a large heterogeneously enhancing tumor. Transarterial chemoembolization (TACE) (b) was performed as a bridge to liver transplantation. Coronal contrast-enhanced CT image (c) after two sessions of TACE demonstrated a large tumor necrosis with subsequent significant reduction of AFP.