Keywords
pediatric - liver tumor - interventional radiology
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
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.
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.
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.
Endovascular Interventions
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]
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.
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.
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.
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]
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]
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.
