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Review Article
Management of Hepatoblastoma in the Modern Era and Future Perspectives
Clin Pediatr Hematol Oncol 2020;27:43-54.
Published online April 30, 2020
© 2020 Korean Society of Pediatric Hematology-Oncology

Jin Kyung Suh, Sunghan Kang, Hyery Kim, Kyung-Nam Koh and Ho Joon Im

Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
Correspondence to: Kyung-Nam Koh
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul 05505, Korea
Tel: +82-2-3010-5994
Fax: +82-2-473-3725
Received April 4, 2020; Revised April 14, 2020; Accepted April 14, 2020.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Hepatoblastoma is the most common malignant hepatic tumor in infants and young children and accounts for approximately 1% of all pediatric malignancies. A treatment strategy incorporating chemotherapy and surgical resection has evolved based on the results of the multicenter clinical trials performed by the major liver study groups during the last two decades and led to significantly improved survival outcomes. The alpha-fetoprotein level, PRE-Treatment EXTent tumor stage, and histological category are well-known prognostic factors that are used for risk stratification. Platinum-based chemotherapy regimens are effective in terms of increasing the likelihood of surgical resectability. Refinement of surgical techniques and the advent of liver transplantation have improved the outcomes in patients with advanced tumors. However, the optimal treatment strategy for advanced hepatoblastoma remains unclear. Unanswered questions include the optimal timing and indications for pulmonary metastasectomy and when the surgical strategy should be complex liver resection or liver transplantation. The major liver study groups have now formed a global coalition known as the Children’s Hepatic tumors International Collaboration and developed an international staging system. The aim of this article is to review current treatment strategies of hepatoblastoma focusing on high risk patients.
Keywords: Hepatoblastoma, Risk stratification, Chemotherapy, Surgical resection

Hepatoblastoma (HB) is the most common pediatric liver malignancy and accounts for over 90% of primary hepatic malignancies in children under the age of 5 years. The estimated annual incidence is 1.5 cases per million and has been increasing over the past two decades, partly because of improved survival rates in premature and low-birth-weight infants. HB mostly affects children younger than 3 years of age and typically presents as a large abdominal mass with an elevated alpha-fetoprotein (AFP) level [1]. The prognosis is determined by the surgical resectability of the primary tumor, whether or not metastatic disease is present, and tumor histology. The treatment strategy is based on risk stratification according to prognostic factors. In recent decades, four leading liver study groups (COG, Children’s Oncology Group; SIOPEL, International Childhood Liver Tumours Strategy Group; GPOH, German Society for Pediatric Oncology and Hematology, and JPLT-2, Japanese Study Group for Pediatric Liver Tumors) have implemented risk-stratified multimodal treatment strategies, including CDDP (cisplatin)-based chemotherapy, which have improved the patient survival rate from 30% to 70-80% [2]. Event-free survival (EFS) is now estimated to be up to 90%, particularly in low-risk patients [2]. This progress has been possible because of not only evolution of chemotherapeutic strategies but also refinement of the surgical techniques used, including liver transplantation (LT). However, despite these improvements, EFS remains low at less than 50% in high-risk patients [2]. In this article, we provide an overview of the current guidelines and recent treatment updates with special consideration of high-risk HB.


1) Alpha-fetoprotein

The serum AFP level is a sensitive biomarker of active and viable HB. AFP is a 70-kDa glycoprotein synthesized in the fetal yolk sac, liver, and gastrointestinal tract and has a half-life of 5-7 days [3]. Most children with HB have a markedly elevated AFP level at diagnosis. AFP is also a useful marker when monitoring the response to therapy and for detecting recurrence after treatment. Serial AFP measurements in a pediatric population with HB showed a decline of <1 log after the first cycle of chemotherapy and preoperative AFP levels in the highest tertile as well as a significant association between postoperative AFP levels in the highest tertile and treatment failure [4]. Another study in patients with high-risk HB found that poor post-surgical outcomes were more significantly associated with a high AFP level (≥3,642 ng/mL) before surgical resection than with any other prognostic factor, including vascular invasion and pathology [5]. The AFP value is a reliable predictor of outcome; a normal or low level (<100 ng/mL) or a very high level (>1.2×106 ng/mL) predicts a negative outcome [6,7]. Therefore, the AFP value should be checked regularly during treatment, especially at the time of diagnosis, before and after surgery, and at the end of treatment.

2) Imaging

Conventional ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) are widely used in the diagnostic workup of HB. Ultrasound is helpful for identifying the presence of a malignant lesion when necrosis, calcifications, or high-velocity flow within the lesion is detected. CT or MRI must be performed for Pre-Treatment EXTent of tumor (PRETEXT) or Post-Treatment EXTent of tumor (POSTTEXT) staging. Contrast-enhanced CT with arterial and portal venous phase is the most widely used imaging modality. CT is convenient, can be performed rapidly, and allows assessment of pulmonary lesions. MRI delineates the vascular anatomy of the tumor more accurately and the margin of the mass more precisely. Therefore, MRI may be a useful tool for preoperative planning. The advent of hepatocyte-specific MRI contrast agents, including gadoxetate disodium (Gd-EOB-DTPA, Eovist/Primovist; Bayer, Leverkusen, Germany) and gadopentetate dimeglumine (Gd-BOPTA, MultiHance; Braco, Milan, Italy) have allowed more accurate PRETEXT staging and identification of vascular involvement, satellite lesions, and tumor infiltration of the biliary trees [7,8]. Furthermore, chest CT is required at diagnosis to detect distant metastasis given the propensity of HB to metastasize to the lungs. Other imaging modalities, such as bone scanning, MRI of the brain, and positron emission tomography (PET)-CT should be reserved for symptomatic patients or, in the case of PET-CT, for assessment of treated patients with a rising AFP level and an unidentified tumor source [8].

3) PRETEXT staging

PRETEXT staging at diagnosis is crucial for risk stratification in patients with HB. Several trials have confirmed that the PRETEXT group is a powerful predictor of overall survival in children with HB [9,10]. This staging method was initially devised by SIOPEL for its first trial (SIOPEL 1 in 1992, updated in 2007) [2,8,11]. In 2017, a new version of the PRETEXT staging system was devised for the international collaborative Pediatric Hepatic International Tumor Trial (PHITT), which standardized the assessments used in PRETEXT staging in each study group, particularly SIOPEL and COG. While the same manner was applied to PRETEXT grouping across the major study groups, different manners were applied to define the annotation factors. The revised 2017 PRETEXT staging system applies more unified and specific criteria to standardize each annotation factor [8]. PRETEXT stage describes the extent of tumor before treatment in four groups (I, II, III, and IV) with annotations of V, P, E, F, R, C, N, and M. PRETEXT group is assigned by the number of sections affected by tumor growth (Fig. 1). The annotation is determined by hepatic venous or inferior vena cava involvement (V), portal venous involvement (P), extrahepatic disease contiguous with the main liver tumor (E), multifocality (F), tumor rupture (R), caudate (C), lymph node metastasis (N), and distant metastasis (M) (Table 1). The same classification criteria are used to evaluate the post-treatment extent of HB (POSTTEXT) after chemotherapy. POSTTEXT staging should be assessed about 10 days after each alternate cycle of chemotherapy. While PRETEXT staging is strictly related to the prognosis, the POSTTEXT stage is the most important factor when planning the surgical resection.

Table 1 . PRETEXT annotation factors revised by the international collaborative Pediatric Hepatic International Tumor Trial (PHITT). Adopted from [8].

FactorAnnotationa)Positive definition
Hepatic venous/inferior vena cava involvementVAny of the following criteria is met

1) Tumor obliterates all 3 hepatic veins or intrahepatic inferior vena cava.

2) Tumor encases by >50% or 180° all 3 hepatic veins or intrahepatic inferior vena cava.

3) Intravascular tumor thrombus in any 1 of all 3 hepatic veins or intrahepatic inferior vena cava.

Portal venous involvementPAny of the following criteria is met

1) Tumor obliterates Rt. and Lt. portal vein or main portal vein.

2) Tumor encases by >50% or 180° Rt. and Lt. portal vein or main portal vein.

3) Intravascular tumor thrombus in any 1 of Rt. and Lt. portal vein or main portal vein.

Extrahepatic spread of diseaseEAny one of the following criteria is met:

1) Tumor crosses boundaries/tissue planes.

2) Tumor is surrounded by normal tissue more than 180°.

3) Peritoneal nodules (not lymph nodes) are present so that there is at least 1 nodule measuring 10 mM or larger or at least 2 nodules measuring 5 mm or larger.

MultifocalityFTwo or more discrete hepatic tumors with normal intervening liver tissue
Tumor ruptureRFree fluid in the abdomen or pelvis with one or more of the following findings of hemorrhage

1) Internal complexity/septations within fluid.

2) High-density fluid on CT (>25 HU).

3) Imaging characteristics of blood or blood degradation products on MRI.

4) Heterogeneous fluid on ultrasound with echogenic debris.

5) Visible defect in tumor capsule.

Tumor cells are present within the peritoneal fluid
Rupture diagnosed pathologically in patients who have received an upfront resection
Caudate involvementCTumor involving the caudate
Lymph node metastasisNAny one of the following criteria is met:

1) Lymph node with short-axis diameter of >1 cm.

2) Portocaval lymph node with short-axis diameter >1.5 cm.

3) Spherical lymph node shape with loss of fatty hilum.

Distant metastasisMAny one of the following criteria is met:

1) One non-calcified pulmonary nodule greater than or equal to 5 mM in diameter.

2) Two or more non-calcified pulmonary nodules, each greater than or equal to 3 mM in diameter.

3) Pathologically proven metastatic disease.

a)All annotation factors are described as positive or negative..

CT, computed tomography; HU, Hounsfield units; MRI, magnetic resonance imaging..

Figure 1. PRETEXT group I, II, III, IV. These four groups reflect hepatic parenchymal tumor involvement. When assessed at diagnosis they are PRETEXT. When assessed after neoadjuvant chemotherapy, but before surgical resection, they are called POST-TEXT. The group is defined by the number of contiguous whereas sections of liver that are tumor free. Left lateral section=Couinaud segments 2 and 3. Left medial section=Couinaud segment 4. Right anterior section=Couinaud segments 5 and 8. Right posterior section=Couinaud segments 6 and 7. Involvement of couinaud segment 1, the caudate lobe, is designated as an annotation factor “C”. Adopted from [13,18].

4) Biopsy

Histologic confirmation on biopsy is mandatory in the diagnosis of HB. Generally, ultrasound-guided needle biopsy is preferable to upfront surgical excision. However, in certain cases, upfront surgical resection at diagnosis is recommended. COG AHEP 0731 recommended upfront surgical resection at diagnosis for PRETEXT I-II tumors with no evidence of macrovascular invasion, defined as at least a 1-cm free tumor margin from the middle hepatic vein, retrohepatic inferior vena cava, and portal bifurcation [12].

Multicenter Clinical Trials and Current Treatment Guidelines

The multimodal risk-stratified treatment strategy using CDDP-based adjuvant and neoadjuvant chemotherapy and surgery for HB has been well established in the multicenter clinical trials performed by the four major study groups. The risk stratification categories used by each group are summarized in Table 2. Although the categories used by these groups are different, they all involve PRETEXT and POSTTEXT staging, tumor biology, presence of metastasis, and response to neoadjuvant chemotherapy (primary mass reduction, a decrease in AFP level) [7].

Table 2 . Risk stratification schemes of the major study groups [13].

Very low riskPRETEXT I or II, pure fetal histology, and primary resection
Low risk/standard riskPRETEXT I or II any histology primary resectionPRETEXT I, II, and IIIPRETEXT I, II, and IIIPRETEXT I, II, and III
Intermediate riskPRETEXT II, III, IV unresectable at diagnosis V+, P+, E+,SCUPRETEXT IV any PRETEXT with rupture, N1, P2, P2a, V3, and V3a multifocal
High riskAny PRETEXT +AFP level<100 ng/mLAny PRETEXT V+, P+, E+, M+,SCU AFP level <100 ng/mL tumor ruptureAny PRETEXT V+, P+, E+, M+multifocalAny PRETEXT M1, N2 AFP level <100 ng/mL

COG, Children’s Oncology Group; GPOH, German Society for Pediatric Oncology; JPLT, Japanese Study Group for Pediatric Liver Tumors; PRETEXT, pretreatment extent of disease; AFP, alpha-fetoprotein; SIOPEL, International Childhood Liver Tumors Strategy Group; SCU, small cell undifferentiated histology..

1) Chemotherapy

The results of the clinical trials suggest that standard and low-risk patients can be treated successfully by CDDP alone or combined with 5-fluorouracil and vincristine whereas high-risk patients require more intensive chemotherapy with doxorubicin, carboplatin, and dose-dense CDDP (Table 3). Patients who receive neoadjuvant chemotherapy should be reassessed after two cycles of treatment by POSTTEXT staging and measurement of the AFP level to define surgical resectability and to determine whether or not further chemotherapy or metastasectomy is needed [12]. A study of the effect of neoadjuvant chemotherapy on resectability found that the majority of stage III and IV HBs either did or did not achieve radiologic resectability after two cycles of chemotherapy and that further chemotherapy did not change this outcome [13,14].

Table 3 . Current treatment strategies of the major study groups [2].

Study groupRisk groupChemotherapySurgery
COG (AHEP 0731)Very low riskNonePrimary
Low riskCDDP, 5FU, VCR×2Primary
Intermediated riskCDDP, 5FU, VCR, Doxo×6-8After 2-4 courses
High riskVCR, irinotecan, temsirolimus×2After 4-6 courses
CDDP, 5FU, VCR, Doxo×6
(SIOPEL 6)Standard riskCDDP×6After 4 courses
(SIOPEL 4)High riskCDDP weekly×8, Doxo 3rd weekly×3After 8 CDDP/3Doxo
GPOHStandard riskCDDP, Doxo×3-4After 2-3 courses
High riskCDDP×5 alternating CARBO/Doxo×5 (SIOPEL 3 HR)After 5-7 courses
PRETEXT IICDDP, PIRA×6After 2 courses
PRETEXT III/IV all V+P+E+CDDP, PIRA×5-6 or CDDP, PIRA×2+IFOS/CARBO/PIRA/VP-16×3-4After 3-4 courses
All PRETEXT M+Additional high-dose VP-16/CARBO/MELAfter 4 courses

5-FU, 5-fluorouracil; CARBO, carboplatin; CDDP, cisplatin; COG, Children’s Oncology Group; Doxo, doxorubicin; VP-16, etoposide; GPOH, German Society for Pediatric Oncology; HR, high risk; IFOS, ifosfamide; JPLT, Japanese Study Group for Pediatric Liver Tumors; MEL, Melphalan; PIRA, pirarubicin; PRETEXT, pretreatment extent of tumor; VCR, vincristine..

2) Surgical treatment

Complete surgical resection is required to achieve a definitive cure in HB. Chemotherapy is administered to achieve resectability. Surgical extirpation of an HB includes segmentectomy, sectionectomy, and/or hemihepatectomy for PRETEXT I and II, trisectionectomy for PRETEXT III and IV, or LT for tumors with bilobar portal vein or hepatic vein and inferior vena cava invasion or extensive loss of normal parenchyma [7,15]. There has been some disagreement between SIOPEL and COG with regard to complete surgical resection at diagnosis. The SIOPEL group recommends four cycles of neoadjuvant chemotherapy for all patients who undergo surgical resection. In contrast, the COG group recommends complete surgical resection at diagnosis when possible. The current COG trial (AHEP 0731) recommends upfront surgical resection at diagnosis for PRETEXT I or II tumors with no evidence of macrovascular invasion, defined as at least a 1-cm free tumor margin from the middle hepatic vein, retrohepatic inferior vena cava, and portal bifurcation [12,13]. For high-risk HB, the current COG guidelines recommend resection by lobectomy or trisegmentectomy after neoadjuvant chemotherapy for PRETEXT III and/or POSTTEXT I, II, or III tumors without venous and portal vein involvement [V (−) and P (−)]. Early referral to a liver specialty center with the ability to perform complex hepatic resection or LT before or during neoadjuvant chemotherapy is recommended for multifocal or PRETEXT III lesions with V (+) or P (+) and PRETEXT IV lesions [7,13,16]. The SIOPEL protocols recommend neoadjuvant chemotherapy for all tumors, followed by restaging and tumor resection based on POSTTEXT assessment using the same recommendations as COG. Adjuvant chemotherapy can be administered postoperatively in not only high-risk patients but also low-risk patients [7]. It is possible that some patients with PRETEXT I or II disease who undergo primary resection may derive benefit from reduced cycles of chemotherapy postoperatively. When a patient presents with rupture of the primary tumor, initial control of hemorrhage followed by a staged hepatectomy after chemotherapy allows effective management by reducing both the tumor volume in the liver and the risk of seeding of the peritoneum at the time of rupture [17].

Recent Collaborative International Studies

To date, it has been difficult to compare the results of studies performed by the different research groups because of variations in risk stratification methods, the surgical strategy used for high-risk HB, and the chemotherapeutic agents used, as well as controversy regarding upfront surgical resection. Therefore, the SIOPEL, COG, and JPLT groups have formed the Children’s Hepatic Tumors International Collaboration (CHIC) to promote closer cooperative research on HB [8,18,19].

1) Children’s hepatic tumors international collaboration–hepatoblastoma stratification

The current risk stratification categories shown in Table 2 vary between the four study groups. In 2013, the CHIC created a shared international database to identify novel prognostic factors that would allow development of a common risk stratification scheme for HB. The CHIC database includes information on 1605 children in eight multicenter HB trials who received CDDP-based chemotherapy and underwent complete surgical resection over a period of 25 years. The CHIC study analyzed the PRETEXT staging by central review of tumor imaging (CT or MRI). The initial univariate analysis identified the following factors to be associated with poor outcomes in children with HB: PRETEXT IV stage, macrovascular hepatic or portal involvement, contiguous extrahepatic disease, multifocality of the primary tumor, metastatic disease, tumor rupture, a low (<100 ng/mL) or high (>1 million ng/mL) AFP level at diagnosis, age ≥8 years, low birth weight (<1,500 g), prematurity, and comorbidity (Beckwith-Wiedemann syndrome) [12,19]. Based on these prognostic factors, the CHIC group recently developed a new HB risk-stratified staging system (CHIC–HS) that includes five levels, use of which showed the 5-year EFS rate to be 86% for PRETEXT I/II, 82% for PRETEXT III, 60% for PRETEXT IV, 42% for metastatic disease, and 35% for an AFP level ≤100 ng/mL at diagnosis [18]. Age at diagnosis, AFP level, and PRETEXT stage remained statistically significant prognostic factors in all subgroups [18]. Based on these variables, each patient is assigned to a risk group, which defines his/her prognosis as very low/low risk (EFS, 89%), intermediate risk (EFS, 50-88%), or high risk (EFS, <50%) (Table 4) [18]. CHIC-HB stratification is a potentially useful tool for determining the prognosis in children diagnosed with HB and is currently being validated in the PHITT trial [8,12]. Moreover, the new CHIC risk stratification strategy might potentially direct therapeutic management of HB. In the CHIC–HS, the presence of metastatic disease at diagnosis is defined as “high-risk” independent of PRETEXT staging and has been found in 20% of the study population. For the subgroup of children with metastatic HB, the AFP level was identified as the most significant prognostic factor: the 5-year EFS rate was significantly lower in patients with an AFP level of 100-1,000 ng/mL at diagnosis than in those with an AFP level of >1,000 ng/mL at the time of diagnosis (18% vs 47%; P<0.0001) [18]. The second most significant prognostic factor for metastatic HB was age at presentation, with a worse prognosis in children aged ≥8 years. Finally, PRETEXT stage III-IV and the presence of one or more PRETEXT annotation factors (such as involvement of the inferior vena cava and portal vein, extrahepatic contiguous tumor extension, multifocal liver lesions, or tumor rupture at diagnosis) were also associated with inferior outcomes [18,19].

Table 4 . Risk stratification of Children’s Hepatic tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS).

Very low/low riskIntermediate riskHigh risk
PRETEXT I/IIAge <3 yearsAge 3-7 yearsAge ≥8 years
PRETEXT IIIAge <8 years, AFP>1,000 ng/mL, VPEFR negativea)Age <8 years, AFP>1,000 ng/mL, VPEFR positiveb)Age ≥8 years
Age <8 years AFP 101-1,000 ng/mL
PRETEXT IVAge <3 years, VPEFR negativeAge <3 years, VPEFR positiveAge ≥3 years
Metastatic diseaseAll
AFP≤100 ng/mLAll

a)The aggregate PRETEXT annotation factor was defined as negative if none of these factors was present..

b)The aggregate PRETEXT annotation factor was defined as positive if at least one of these factors was present..

PRETEXT, pretreatment extent of tumor; AFP, α fetoprotein..

2) Pediatric hepatic international tumor trial

The CHIC-HS will be included in PHITT, a randomized interventional study that is using a stratification approach to investigate the outcomes of 1) reduction of chemotherapy in patients with low-risk HB, 2) intensification of treatment with novel agents in high-risk patients, and 3) comparison of three different regimens in intermediate-risk patients. A key strand of PHITT is an evaluation of the biology of HB using identification/validation of novel and already reported prognostic biomarkers as well as toxicity biomarkers. PHITT will also evaluate the impact of a surgical planning instrument on the decision-making process in POSTTEXT III and IV HB. The results of PHITT are expected to provide a practical tool that will facilitate personalized treatment in children with HB in terms of both the chemotherapy regimen and the surgical approach [12].

Special Considerations on the Treatment of High-Risk Hepatoblastoma

1) Surgical treatment strategy: resection versus transplantation

Pediatric patients with unresectable HB occupying multifocal segments and/or involving the main vascular trunk are candidates for LT. The current COG protocol (AHEP 0731) recommends early consultation with a transplant center in order to treat unresectable HB with PRETEXT IV, unifocal centrally located PRETEXT II and III involving the main hilar structures, or all three of the main hepatic veins; some of these patients require primary LT or complex resection after chemotherapy [13,20]. Primary LT for such unresectable HBs has improved the outcomes, with a patient survival rate of 77-82% [5, 21-23]. However, some studies have suggested the possibility of resection for PRETEXT/POSTTEXT III and IV HB, with excellent overall survival rates of 80-88% [24,25]. LT is also useful in the setting of intrahepatic recurrence or residual tumor after an attempt at partial hepatectomy. However, rescue LT, which is performed when conventional surgical resection has failed, has a lower survival rate (approximately 30%) while primary LT has a superior survival rate (approximately 80%) in high-risk HB [21]. Controversy continues regarding the best treatment for tumors that are very large or critically positioned and impinge on essential vascular structures. A randomized trial comparing complex resection and primary LT for these advanced HBs has not yet been performed; in the meantime, the decision regarding the best approach lies in the hands of the surgical team [13]. Generally, children undergoing LT receive adjuvant chemotherapy. However, several studies have reported equally good results regardless of whether or not adjuvant chemotherapy is administered after LT [26-28]. There is no clear policy concerning the role of adjuvant chemotherapy after LT. LT is indicated in patients with chemotherapy-responsive multifocal disease, given that radiographic imaging cannot ensure complete resolution of microscopic foci. A Japanese study that compared the outcomes of complex surgical resection with those of LT suggested that primary LT rather than complex resection was preferable for high-risk HB with a poor response to neoadjuvant chemotherapy, even if the tumor can be resected in view of the possibility of vascular invasion or microscopic residual tumor [5]. In that study, patients who responded poorly to neoadjuvant chemotherapy received adjuvant irinotecan after LT while those who responded adequately received CDDP-based adjuvant chemotherapy [5]. Unresectable or progressive extrahepatic metastatic disease, including persistent pulmonary lesions that do not respond to chemotherapy, is an absolute contraindication to LT [13]. However, patients with metastasis at the time of diagnosis are still eligible for LT if these lesions regress with preoperative chemotherapy or are surgically resected [29,30]. The most common complication after LT is vascular thrombosis, followed by local recurrence, pulmonary metastatic disease, and bile leak. PET-CT imaging is recommended before LT to detect preexisting pulmonary metastatic disease, which may be missed on conventional CT imaging [7,13,31]. Postoperative management of these children, including immunosuppression regimens, requires further investigation.

2) Hepatoblastoma with lung metastasis

Approximately 10-20% of patients with HB present with lung metastasis at diagnosis, and the overall survival of these patients has ranged from 25% to 50% [32,33]. Tables 5 and 6 show the results of a systematic review of the outcomes and characteristics of HB with lung metastasis across the different clinical trials. The outcomes have significantly improved due to intensification of chemotherapy, which has increased the response of metastasis to chemotherapy from 31% to 97%. All patients received neoadjuvant chemotherapy before any surgical treatment and 43.5% had a complete response after chemotherapy. Of 91 patients (21%) who underwent surgical resection of lung metastasis, 25 (27.5%) had metastasectomy after primary tumor surgery, 22 (24.2%) before (mainly proceeding to LT), and 14 (15.4%) at the same time as primary tumor surgery [12]. A report on lung metastasis in the COG AHEP 0731 trial revealed that number of nodules (≥10) and total burden of metastasis (≥22 mM) increased the risk of events but laterality (bilateral vs. unilateral) did not [34]. In that study, given that lesions that fail to meet RECIST size criteria (<10 mM) at diagnosis may contain viable tumor whereas residual lesions at the end of therapy may constitute eradicated tumor/scar tissue, radiological criteria alone did not seem to be the optimal method for evaluating the disease response of lung metastasis. Therefore, the decision regarding treatment for metastatic HB should consider the presence of lesions on imaging evaluation as well as the total nodule burden, change in size over time, lesion stability, and the serum AFP level [12]. In all the protocols, HB with lung metastasis at diagnosis is treated with neoadjuvant chemotherapy followed by surgical resection of the primary tumor and/or lung metastasis depending on resectability and the response to chemotherapy [12,34, 35]. Metastasectomy is known to be beneficial in two distinct populations of patients: those whose metastasis fails to clear with chemotherapy, especially if proceeding to LT, and those who achieve a complete response and then develop a pulmonary relapse [12].

Table 5 . Response and outcomes in hepatoblastoma with lung metastasis, across the multicenter trials of major study groups [12].

StudyResponse to chemotherapyOutcomes

N of metastatic patientsNon-resected at diagnosis (%)Responders to NAC (%)Eligible for delayed final resection (%)Resectable after NAC (%)EFS (%)OS (%)
COG AHEP-07312910031-6949 (3 years)62 (3 years)
JPLT-23510043--21 (5 years)44 (5 years)
SIOPEL-43967.69788.79577 (3 years)79 (3 years)
SIOPEL-37098.771839156 (3 years)62 (3 years)
SIOPEL-225-7260--44 (3 years)
SIOPEL-231-84--28 (5 years)57 (5 years)
INT-00984098.4-57.14725 (5 years)37 (5 years)
POG-934511--36-27 (5 years)27 (5 years)

NAC, neoadjuvant chemotherapy; EFS, event-free survival; JPLT, Japanese Study Group for Pediatric Liver Tumors; N, number; POG, Pediatric Oncology Group; SIOPEL, International Childhood Liver Tumour Strategy Group..

Table 6 . Characteristics of hepatoblastoma patients who presented with lung metastasis [12].

Hepatoblastoma with lung metastasisN (%, range)
Total patients434
Lung metastasis cleared after NAC189 (43.5)
Lung metastasectomy91 (21)
Timing of lung metastasectomy
Before primary tumor surgery22 (24)
After primary tumor surgery25 (28)
Simultaneous to primary tumor surgery14 (15)
Not specified30 (33)
Primary tumor surgery
Yes407 (94)
No27 (6)
Type of primary tumor surgery
Liver resection183 (45)
LT61 (15)
Not specified163 (40)
Median time to last follow up, years4 (1-12)
Overall survival rate83 (0-100)
Overall rescue rate40 (0-100)

NAC, neoadjuvant chemotherapy; LT, liver transplantation; N, number..

3) Optimal strategy for lung metastasis: when and how

It is generally recommended that lung metastasis should be treated with chemotherapy first and that patients with residual disease after chemotherapy or a pulmonary relapse are candidates for lung metastasectomy, given that lung metastasis of HB usually responds to chemotherapy [34-36]. Remnant or relapsed lesions after chemotherapy should be aggressively resected. A Japanese report on pulmonary metastasis showed that patients who underwent multiple pulmonary metastasectomies achieved long-term survival in spite of multiple relapses [37]. Furthermore, lung metastasis should be resected before LT. The only absolute contraindication to pulmonary metastasectomy would be inadequate pulmonary function [38]. The optimal timing of lung metastasectomy (before, after, or at the same time as surgical resection of the primary tumor) and the optimal surgical approach to lung metastasis is still under debate. Most surgeons prefer to perform pulmonary metastasectomy after resection of the primary tumor because control of the primary HB is associated with improved outcomes [35,36]. Moreover, HB cells may synthesize hepatocyte growth factor, levels of which appear to increase after surgical resection, with subsequent stimulation of growth, invasion, motility, angiogenesis, and prolonged survival of tumor cells [12]. In view of this concept, a German group proposed simultaneous resection of the primary tumor and lung metastasis as single-stage surgery. They showed that all 7 patients with metastatic HB at diagnosis achieved complete resolution of lung metastasis at the time of liver surgery (the number of metastasis removed ranged from 1 to 8; in 3 cases, lung lesions were bilateral). At the 5-year follow-up, 2 (28.6%) patients had experienced relapses and the overall survival rate was 83% [39]. There are no data on surgical complications after lung metastasectomy in HB to inform the optimal surgical approach in these patients. However, significant experience of the surgical treatment of pulmonary metastasis in patients with other pediatric solid tumors shows that unilateral thoracotomy, bilateral thoracotomy, or median sternotomy are well tolerated in children. Lung wedge resection is recommended (independent of the surgical approach) to provide adequate residual lung function. There is no clear limit to the number of metastases that can be resected; therefore, in terms of the decision strategy, the aim of each surgery is to achieve clear lungs [12,38]. For small lesions that are not palpable or are invisible, indocyanine green navigation surgery, using a fluorescence imaging system and CT-guided localization followed by video-assisted thoracoscopic surgery, is useful for lung metastasectomy in HB.

Conclusions and Future Perspectives

Generally, PRETEXT I or II tumors can be primarily resected after chemotherapy using CDDP-based regimens (CDDP alone or combined with vincristine, 5-fluorouracil, or pirarubicin) while PRETEXT III or IV tumors should be treated with a more intensive regimen that includes doxorubicin or dose-dense CDDP. Patients with PRETEXT III-IV tumors and vascular involvement should be considered candidates for primary LT (Figs. 2 and 3). This risk-stratified treatment strategy, which includes chemotherapy and surgery, has improved the survival rate to 70-80% from a rate of less than 30% before introduction of chemotherapy. However, the risk stratification categories and treatment strategies vary between the present study groups. Several controversies regarding the treatment of HB have arisen from these disparities, including 1) the need for neoadjuvant chemotherapy and its optimal duration, 2) optimal surgical treatment for locally advanced tumors (aggressive hepatic resection versus LT), 3) the role of adjuvant chemotherapy after LT, and 4) the timing and role of metastasectomy. Unified global studies (CHIC, PHITT) are underway to resolve these controversies.

Figure 2. Decisional algorithm based on current protocols in pediatric patients with advanced hepatoblastoma. HB, hepatoblastoma; SCU, small cell undifferentiated histology; NAC, neoadjuvant chemotherapy; DOXO, doxorubicin.
Figure 3. Decisional algorithm based on current protocols in pediatric patients with hepatoblastoma and lung metastasis. Adopted from [12]. HB, hepatoblastoma; NAC, neoadjuvant chemotherapy; ACT, adujuvant chemotherapy; TACE, transarterial chemoembolization; RFA, radiofrequency ablation; HIFU, high-intensity frequency ultrasound.
Conflict of Interest Statement

The authors have no conflict of interest to declare.

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  • Kyung-Nam Koh