Hepatoblastoma is the most common malignant liver tumor in childhood. The majority of the cases are seen in children less than five years of age, [3] with the incidence among children less than one year, being 10.5 per million. However, in the 1–4 years age group, it falls to 5.2 per million and for the above 4 years age group, it is too infrequent to be considered significant. [4]. The histologic resemblance of HB cells to embryonal liver cells and the necessity for a latent period, strongly suggest initiation during gestation. [5]
There is an evident association of hepatoblastoma with various inherited syndromes like Familial adenomatous polyposis, Beckwith-Wideman Syndrome, Trisomy 18, Neurofibromatosis 1, Prader Willi Syndrome, DiGeorge syndrome and various others. [6] Also, low birth weight (< 1500 mg) has been associated with an increased incidence of hepatoblastoma. It has also been associated with preeclampsia, polyhydramnios and the use of fertility drugs. Maternal or paternal smoking along with the timing of exposure (pre- or post-conception) has also been proven to have an association. However, investigations of the Hepatitis B virus or alcohol have surprisingly yielded no significant association. [5] In the present series, no specific association was observed with any risk factors or inherited syndromes.
The most common clinical presentation includes abdominal mass and distension as was seen in our series, often associated with abdominal discomfort, vomiting, severe anaemia and fatigue among others. [7] Rare manifestations also include pseudo-precocious puberty (due to chronic GnRH secretion). Serum AFP remains the key biochemical marker for establishing the diagnosis, with normal values in biopsy-proven cases being a poor prognostic factor. [4] Ultrasonography usually reveals a large mass with areas of necrosis and hemorrhage within. However, Triphasic CT scan remains the most valuable diagnostic modality with a well-defined heterogeneous mass which is hypoattenuating with infrequently seen dense calcifications. [8] This was corroborated well in our study, with accurate PRETEXT staging of the disease confirmed on operative findings. Magnetic resonance imaging (MRI) is superior in defining margins or vessel involvement with hyperintense lesions in T2. A tru-cut biopsy is usually suggested in all cases, but some groups advocate avoiding biopsy in cases with high AFP and in age groups of 6 months to 3 years. The tumors can be subclassified as pure fetal epithelial, mixed embryonal and fetal epithelial, macro trabecular, SCUD (Small cell undifferentiated) and MEM (Mixed epithelial and mesenchymal) with or without teratoid features. Among these, the most common epithelial subtype is fetal (43.2%) as was seen in our series, with five out of six patients having a fetal subtype and the remainder being mixed embryonal and fetal epithelial. These patients with fetal subtype have a relatively decreased incidence of microvascular invasion, recurrence, metastasis and death. [9] SIOPEL has developed a PRETEXT staging based on radiological imaging findings. [10] The stages are further subclassified in low, intermediate and high risk based on the following annotations: VPEFRM (V- IVC or hepatic veins involvement; P – Portal Vein involvement; E – contiguous extrahepatic intraabdominal extension; F – multifocal tumor; R – Rupture; M – Metastasis), AFP levels (< 100 ng/ml; 101 to 1000 ng/ml; 1001 to 1000000 ng/ml; >1000000 ng/ml) and age (0 to < 1 years; 1–2 years; 3–7 years; >8 years). Based on these, a comprehensive risk stratification system CHICS (Children’s Hepatic Tumors International Collaboration) [11] has been created which subclassifies these patients into standard/low risk, high risk and very high risk in terms of treatment protocols. [12] (Table 3)
Table 3
CHICS classification (V- IVC or hepatic veins involvement; P – Portal Vein involvement; E – contiguous extrahepatic intraabdominal extension; F – multifocal tumor; R – Rupture; M – Metastasis) [13]
|
Standard Risk
|
|
|
PRETEXT
|
Low Risk
|
Intermediate Risk
|
High Risk
|
Very High Risk
|
Any M+
|
0
|
0
|
0
|
M+
|
I
|
VPERF -
|
0
|
VPERF + and Age < 8 years
|
VPERF + and Age > 8 years
|
II
|
VPERF - AND Age < 3years AND AFP > 1000 ng/ml
|
VPERF - AND Age < 3years AND AFP 100–1000 ng/ml
|
Age 3–7 AND/OR VPERF +
|
AFP < 100 ng/ml AND/OR Age > 8 years
|
III
|
0
|
VPERF - AND Age < 3years AND AFP > 1000 ng/ml
|
Age 3–7 AND/OR VPERF + AND/OR AFP 100–1000 ng/ml
|
AFP < 100 ng/ml AND/OR Age > 8 years
|
IV
|
0
|
0
|
AFP > 100 ng/ml
|
AFP < 100 ng/ml AND/OR Age > 8 years
|
Standard/low risk with PRETEXT I, II or sometimes III can usually undergo complete surgical resection if the tumor is at least 1 cm from the middle hepatic vein and portal vein bifurcation. Other such cases will require two to four cycles of preoperative chemotherapy followed by surgical resection and two cycles of postoperative chemotherapy. High-risk patients require dose-intensive chemotherapy with a platinum-based agent combined with doxorubicin, followed by a re-evaluation for surgical resection. Very high risk is characterized by metastatic tumors, age > 8 years or AFP < 100 ng/ml. Patients are treated with dose-intensive weekly cisplatin/doxorubicin therapy or any alternative therapy and then re-evaluated. In addition, orthotopic liver transplantation has proven to have improved the outcomes for patients with PRETEXT IV unresectable tumors or those with portal vein or hepatic vein involvement. [7]
In Table 4, we review various studies done on the management of hepatoblastoma to date and analysed their results. A common observation among these series is that preoperative chemotherapy and appropriate risk stratification can help achieve improved survival in these patients, which was corroborated by the results of our study.
Table 4 - A literature review of the various case series and articles published on hepatoblastoma
Author
|
Study period
|
N
|
Age
|
Sex
|
PRETEXT
|
CHICS
|
Mets
|
AFP Pre-Chemo (ng/ml)
|
Chemo-therapy
|
Surgery
|
Patho-logy
|
Survival
|
Follow up
|
Comments
|
Ang et al [14] (2007)
|
1984–2004
|
30
|
19 mo
|
17M/13F
|
I − 3;
II − 17; III − 5; IV − 2; U − 3
|
|
Lung mets − 9
|
60–395,000 times elevated
|
All had NAC as per SIOPEL protocol
|
Upfront surgery − 2; Delayed surgery − 27
|
|
5 year OS − 89.1%; 5 year EFS − 75.7%
|
6.3 yr
|
Increased risk of recurrence and death when microscopic margins positive; Adequate surgical resection with NAC provides good long term outcomes
|
Bajpai et al [15] (2005)
|
|
10
|
27.2 mo
|
7M/3F
|
I − 0;
II − 3; III − 2; IV − 5
|
|
None
|
16,116
|
PLADO (1st line) / 5FU (2nd line)
|
Liver resection after NAC in all pts
|
Fetal − 4; Anaplastic − 3;
Mixed mesenchymal − 3
|
Recurrence in 3 pts; 80% survival rate at 60 mo
|
36.1 mo
|
Preoperative chemotherapy reduces the tumor volume significantly and allows safe radical hepatectomy
|
Kusano et al [16] (2000)
|
1985–1995
|
7
|
30 mo
|
4M/3F
|
|
|
None
|
13,80,000
|
CDDP + ADM
|
Curative resection in 6 pts; palliative resection in 1 pt
|
Embryonal − 2;
Fetal − 4; Mixed − 1
|
6 out of 7 surviving
|
66 mo
|
Perioperative chemotherapy improves the resection rate and OS. DNA ploidy pattern analysis may help in predicting prognosis.
|
Author
|
Study period
|
N
|
Age
|
Sex
|
PRE-TEXT
|
CHICS
|
Mets
|
AFP Pre (ng/ml)
|
Chemo-therapy
|
Surgery
|
Patho-logy
|
Survival
|
Follow up
|
Com-ments
|
Ismail et al [17] (2012)
|
1990–2010
|
51
|
2.9 yr
|
25M/26F
|
II − 17; III − 24; IV − 10
|
SR-38; HR-13
|
Lung mets − 2
|
|
NAC with PLADO / Cisplatin − 40; Upfront surgery − 8; Palliative Chemo − 3
|
Surgery in 48 pts: Resection − 38; LT − 10
|
Fetal − 17; MEF − 13; MEM − 3; SCUD − 3
|
DFS − 72.9%
|
85 mo
|
Unfavorable factors - SCUD; AFP > 1M and < 100; Lung mets and local recurrence after resection. Survival is related to PRETEXT stage. Among III and IV stage pts, LTx results in better survival
|
Liu et al [18] (2019)
|
1996–2014
|
60
|
1.1 yr
|
34M/26F
|
I − 5;
II − 13; III − 22; IV − 4; U − 16
|
SR-35; HR-9; U-16
|
Lung mets − 5
|
< 100 in 2; 100–1000 in 2; 1000-1M in 50; >1M in 6
|
HB/HCC 1996 protocol - Carboplatin / CDDP 1st line; PLADO − 2nd line
|
Upfront surgery − 12; NAC f/b resection − 33, NAC f/b LTx − 3
|
Fetal − 22; MEF − 15; Embryonal − 2; MEM − 9; SCUD − 1
|
14/60 deaths. 5 year OS − 77.7%
|
6.8 yr
|
Pts with HR features should have SIOPEL 3 and 4 chemotherapy.
|
Dall'l-agna et al [19] (2017)
|
1998–2006
|
79
|
< 6 mo
|
26M/53F
|
I − 7;
II − 27;
III − 36; IV − 9
|
SR-62; HR-17
|
|
79,502
|
SIOPEL 2; SIOPEL 3
|
|
|
5 year OS 91%; EFS 87%
|
|
AFP < 100 and Presence of mets negatively affect long term outcomes.
|
Shukla et al [20] (2008)
|
2000–2007
|
18
|
18 mo
|
12M/6F
|
|
|
None
|
3,56,400
|
NAC with PLAVF regimen
|
Resection in all pts after NAC
|
Fetal − 7; MEF − 3; MEM − 3
|
3 recurrences; DFS at 80 mo -67%
|
14 mo
|
Neoadjuvant chemotherapy should be used for downstaging the tumor pre-surgery
|
Author
|
Study period
|
N
|
Age
|
Sex
|
PRETEXT
|
CHICS
|
Mets
|
AFP Pre-Chemo (ng/ml)
|
Chemo-therapy
|
Surgery
|
Patho-logy
|
Survival
|
Follow up
|
Comments
|
Sunil et al [21] (2017)
|
2000–2013
|
12
|
21 mo
|
8M/4F
|
I − 3; II − 1; III − 8
|
SR-10; HR-2
|
Dist-ant mets − 2
|
20,000
|
NAC with 6 cycles of PLADO
|
Resection in 9 pts
|
Embryonal type was most common
|
5 year OS − 91%; Median survival 120 mo
|
96 mo
|
MDT approach and complete resection can lead to good outcomes
|
Teran et al [22] (2014)
|
2003–2011
|
7
|
14.4 mo
|
4M/3F
|
I − 4; II − 2; III − 1
|
|
None
|
14,277
|
5 out 7 had SIOPEL 3 and SIOPEL − 6 chemotherapy
|
Liver resection in 5 pts after NAC; upfront surgery in 2
|
Embryonal / MEF − 3; fetal − 2; MEM − 2
|
All pts alive and disease free
|
23 mo
|
Multimodal management with meticulous surgical approach leads to optimal postoperative results
|
Wu et al [23]
(2022)
|
2008–2018
|
37
|
13 mo
|
25M/7F
|
III − 19; IV − 18
|
|
None
|
< 100–1 pt;
>100 in all others
|
|
Upfront surgery − 18; Surgery after NAC − 19
|
|
3/19 in NAC group had recurrence and 1 had lung mets; 2/18 in upfront surgery group died. 3 year EFS − 79–89%
|
49 mo
|
3 year EFS was higher in pts offered upfront surgery in III/IV PRETEXT pts
|
Author
|
Study period
|
N
|
Age
|
Sex
|
PRETEXT
|
CHICS
|
Mets
|
AFP Pre-Chemo (ng/ml)
|
Chemo-therapy
|
Surgery
|
Patho-logy
|
Survival
|
Follow up
|
Comments
|
Archana et al [24] (2019)
|
2010–2015
|
10
|
11 mo
|
7M/3F
|
I − 3;
II − 3; III − 1; IV − 3
|
SR-6; HR-4
|
Lung mets − 1
|
Elevated in 9/10 pts
|
PLADO in all
|
PLADO followed by surgery in 5 patients.
|
Pure fetal − 3; embryonal − 1; Mixed epithelial − 4; MEM − 2
|
4 lost to follow up; 1 death; surviving − 5
|
|
Histology and grading done as per CAP needs to be revised and PRETEXT should be put in perspective of tumor of grades.
|
Li et al [25]
(2020)
|
2010–2017
|
93
|
11 mo
|
66M/37F
|
I − 0;
II − 36; III − 23; IV − 3; U − 31
|
|
|
76,131
|
NAC − 22; TACE − 25; Combination − 30
|
Liver resection − 93; LT − 0
|
Epithelial − 25.8%; Epithelial mixed − 11.8%; Mixed − 44.1%; Unknown − 18.3%
|
RFS − 90.3%; Recurrence − 9.7%; Mortality − 5.4%
|
30.5 mo
|
No difference in 2 year EFS and OS among NAC and TACE groups
|
Shanmugam et al [26] (2015)
|
2011–2016
|
30
|
34 mo
|
21M/9F
|
I − 1;
II − 13; III − 7; IV − 9
|
SR-15; HR-15
|
Lung mets − 3
|
2,03,018
|
All had NAC as per SIOPEL − 3 protocol
|
Resection − 19; LTx − 6; Palliative chemo − 5
|
Fetal epithelial − 60%; MEM − 33%
|
Recurrence in 4 pts; EFS in SR risk − 93% but in HR − 60%
|
30 mo
|
Complete surgical resection is the cornerstone of Mx. MDT, Inclusion of LTx and standard chemotherapy can improve prognosis.
|
Author
|
Study period
|
N
|
Age
|
Sex
|
PRETEXT
|
CHICS
|
Mets
|
AFP Pre-Chemo (ng/ml)
|
Chemo-therapy
|
Surgery
|
Patho-logy
|
Survival
|
Follow up
|
Comments
|
Our study
|
2013–2020
|
6
|
15 mo
|
4M/2F
|
I − 1;
II − 3; III − 2
|
SR-4; HR-2
|
Lung mets − 1
|
1,55,000
|
NAC as per SIOPEL 3 and 4
|
Resection in all pts after NAC
|
Fetal − 5; MEF − 1
|
No recurrence until last follow-up
|
40.3 mo
|
Use of risk stratification and NAC as per SIOPEL can improve the prognosis
|
Dhali et al [27] (2022)
|
2015–2020
|
23
|
14 mo
|
16M/7F
|
I − 1;
II − 10; III − 11; IV − 1
|
SR-15; HR-7
|
Lung mets − 2
|
8,000 (878–1,280,000)
|
Cisplatin monotherapy − 10; SUPER PLADO − 8; PLADO − 5;
|
Liver resection in all pts following NAC
|
Fetal − 18; MEF = 2; Embryonal − 1; Undifferentiated − 1; MEM − 1
|
Overall survival 73.9% at 3 mo; relapse in 3 pts
|
31 mo
|
Even in resource limited setting, with adoption of multidisciplinary strategy and good surgical clearance, outcomes are good.
|
A limitation of our study is the small sample size and its retrospective nature. To summarize, with the use of risk stratification and further preoperative chemotherapy, the prognosis of hepatoblastoma has significantly improved. This has been reflected by the results of our study where good survival is achieved with the use of preoperative and postoperative chemotherapy as per the SIOPEL and CHICS stratification.